Apparatus, devices and methods for obtaining omnidirectional viewing by a catheter

ABSTRACT

An apparatus for obtaining information regarding a biological structure(s) can include, for example a light guiding arrangement which can include a fiber through which an electromagnetic radiation(s) can be propagated, where the electromagnetic radiation can be provided to or from the structure. An at least partially reflective arrangement can have multiple surfaces, where the reflecting arrangement can be situated with respect to the optical arrangement such that the surfaces thereof each can receive a(s) beam of the electromagnetic radiations instantaneously, and a receiving arrangement(s) which can be configured to receive the reflected radiation from the surfaces which include speckle patterns.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a continuation of U.S. patent application Ser. No.14/309,170 which relates to and claims priority from U.S. PatentApplication Ser. Nos. 61/836,716 filed on Jun. 19, 2013, 61/934,454filed on Jan. 31, 2014, and 61/905,893 filed on Nov. 19, 2013, theentire disclosures of which are incorporated herein by reference.

FIELD OF THE DISCLOSURE

The present disclosure relates generally to viewing by a catheter, andmore specifically, to exemplary embodiments of exemplary devices,apparati and methods for omnidirectional (e.g., laser speckle) imaging,and viewing by a catheter.

BACKGROUND INFORMATION

Despite major advances in coronary interventions and pharmacotherapies,acute myocardial-infarction (“AMI”) remains the leading cause of death,annually claiming over 10 million lives worldwide. AMI can be caused bycoronary thrombosis that can frequently result from the rupture ofvulnerable plaque. If vulnerable plaques could be identified and treatedprior to rupture, the incidence of AMI could be substantially reduced,and tens of thousands of lives could be saved. A key challenge inrealizing this preventative paradigm can be that plaques with vulnerablemorphology occur at multiple sites in the coronary tree, and therefore,additional knowledge of plaque mechanical stability can be imperative inorder to accurately identify plaques with the highest risk of rupture.

Laser speckle patterns (see, e.g., References 96 and 97) can be granularintensity patterns that can arise from the interference of coherentlight scattered from randomly distributed light scattering particles.The scattered photons can experience different path lengths. The phasedifference between partial waves can cause constructive or destructiveinterference, and can produce randomly distributed high or low intensityspots called speckles. The moving scatterers can introduce differentphase shifts for different partial waves, and can change theinterference between partial waves, which can lead to temporally varyingspeckle patterns. The temporal evolution of speckles can provideinformation of scatterers' movement (see, e.g., Reference 98), and canfurther the information of the media properties which can influence thescattering particles motion (e.g., viscoelasticity). (See, e.g.,References 99-103). Laser speckle imaging (“LSI”) techniques have beenapplied in medical diagnosis to retrieve information about tissueperfusion (see, e.g., References 98 and 104), and mechanical properties(see, e.g., References 99-103) of tissues from dynamic speckle patterns.To perform LSI in vivo, coherent light can be delivered via an opticalfiber, and the reflected laser speckle patterns can be collected andtransmitted via optical fiber bundles (“OFB”) incorporated within smalldiameter endoscopes. (see, e.g., References 99-103 and 105-107).

Due to their small transverse dimensions and flexibility, optical fiberbundles have been widely used in medical endoscopy (see, e.g.,References 108-112), and in other minimally-invasive approaches, toenable the capability of being guided through coronaries or otherconduits of human body. The large numerical aperture (“NA”) can compareto the common optical fiber, and high cores density give fiber bundlescan have high light collection efficiency. The high compact density ofcores of fiber bundles can also provide high resolution imaging. Howeverin LSI, the light can be highly coherent unlike the white lightendoscopy (see, e.g., Reference 113 in which the interference effectbetween cores can be neglected. The high density of cores can introducestrong coupling between adjacent fibers, which can severely affect theimage quality transmitted through fiber bundles. Each fiber in the fiberbundles can support multiple guided modes, and the field of these modescan extend into the cladding, and can overlap with the mode fields ofsurrounding fibers. (See, e.g., Reference 114). Such overlapping canlead to the coupling, between modes, of individual fibers, andinterfiber power exchange between adjacent fibers known as the opticalcrosstalk between fibers. Consequently, the transmitted images, or laserspeckles, can be modulated by the inter-fiber crosstalk in fiber bundlesdue to mode coupling. During the in vivo LSI, the movement of fiberbundles due to the bulk motion of surrounding tissue can be hard toprevent. The movement of a fiber bundle can cause the core couplingchanging with time, and the modulation to the transmitted speckles canbe varying with time. As a result, the time-varying coupling betweencores can cause erroneous speckle temporal statistics, and can reducethe accuracy of an LSI analysis. (See, e.g., Reference 100).

The coupling between fibers modes of different fibers in fiber bundleshas been extensively studied based on the fiber core size, core spacing,NA and non-uniformity of cores. (See, e.g., References 115-117). Howeverthese studies mainly focused on the coupling between fundamental modesof neighboring fibers. Only a few numerical simulations (see, e.g.,Reference 118) and experiments (see, e.g., References 100, 116 and 119)have been conducted to show the fiber crosstalk in multimode fiberbundles and its influence on image transmission. These numericalsimulations (see, e.g., Reference 118) only simulated fields propagatinga few mm along the length of bundles due to the intensive computingrequired. Previous experiments have demonstrated leached fiber bundlescan effectively reduce the cross talk between cores, and can obtain arelatively stable temporal decorrelation function of transmittedspeckles during bundles motion because of large core-to-core separationdue to manufacturing processes of leached fiber bundle. (See, e.g.,Reference 100). However, the effect of mode coupling between neighboringoptical fibers on the transmission of laser speckles may not be wellunderstood.

In order to conduct laser speckle imaging via a catheter, light can beguided through an optical fiber and distal optical components toilluminate a single spot on the cylindrical lumen to collect reflectedspeckle patterns via a single fiber or collection of optical fibers(e.g., a fiber bundle). To conduct circumferential mapping, the cathetercan be rotated during pull-back. However, this can introduce motionartifacts during catheter rotation that can confound the ability toaccurately analyze laser speckle patterns from tissue.

Thus, it may be beneficial to provide an exemplary device, apparatus andmethod for viewing by a catheter, which can overcome at least some ofthe deficiencies described herein above.

SUMMARY OF EXEMPLARY EMBODIMENTS

These and other objects of the present disclosure can be achieved byprovision of an apparatus for obtaining information regarding abiological structure(s), which can include, for example a light guidingarrangement which can include a fiber through which an electromagneticradiation(s) can be propagated, where the electromagnetic radiation canbe provided to or from the structure. An at least partially reflectivearrangement can have multiple surfaces, where the reflecting arrangementcan be situated with respect to the optical arrangement such that thesurfaces thereof each can receive a(s) beam of the electromagneticradiations instantaneously, and a receiving arrangement(s) which can beconfigured to receive the reflected radiation from the surfaces whichinclude speckle patterns.

In some exemplary embodiments, a polarizing arrangement(s) can beincluded which can receive the electromagnetic radiation, and preventreceipt of a same polarization from returning to the receivingarrangement(s). The reflective arrangement can have a portion(s) with ashape of a cone, a polygon or a pyramid. An optical arrangement can beincluded which can be configured to receive the electromagneticradiation(s). The optical arrangement can include a GRIN lens, a balllens, or an imaging lens. The number surfaces of the reflectivearrangement can be 2 or more, 4 or more, or 6 or more. The light guidingarrangement can include a configuration which can split theelectromagnetic radiation to further radiations having differentwavelengths where the multiple surfaces can reflect the furtherradiations, and where the receiving arrangement(s) can be furtherconfigured to receive the reflected further radiations provided at thedifferent wavelengths.

In another exemplary embodiment of the present disclosure can be anapparatus for obtaining information regarding a biological structure(s),which can include, for example, a catheter arrangement which can includea fiber(s) through which an electromagnetic radiation(s) can bepropagated, where the electromagnetic radiation can be provided to orfrom the structure. A pullback arrangement can be configured tofacilitate a pullback of the catheter arrangement, and a detectorarrangement can includes a plurality of sensors, the sensors beingcoupled to a surface of a portion(s) of the catheter arrangement, andconfigured to move together with the pullback arrangement, and receiveoptical information associated with the electromagnetic radiation(s)provided from the structure so as to generate the information.

In some exemplary embodiments of the present disclosure, the sensors canbe directly attached to the surface of the portion(s) of the catheterarrangement. The detector arrangement can include a CMOS sensor, a CCDsensor, a photodetector or a photodetector array. The fiber(s) caninclude a plurality of fibers, or a fiber bundle. For example, at anillumination wavelength between about 630-720 nm, the fiber bundle canhave (i) a core diameter of 3.0 μm±0.3 μm with a fluctuation in corediameter of ±0.03 μm to ±0.3 μm, (ii) a numerical aperture of at least0.35, and (iii) a core spacing of 8.0 urn±0.5 μm. The pullbackarrangement can be controlled by a motor(s). The motor(s) can controlthe pullback arrangement such that the pullback arrangement can move thecatheter and detector arrangements in a stepped manner. The motor(s) cancontrol the pullback arrangement to rotate a drive shaft or distaloptics. The motor(s) can be configured to keep the catheter stationary.

In some exemplary embodiments of the present disclosure, adjacent timesfor the movements of the catheter and detector arrangement can bebetween 5 msec and 100 msec. The sensors can receive the opticalinformation that can be associated with the electromagnetic radiationprovided at different wavelengths. A filter arrangement can beconfigured to filter the optical information based on theelectromagnetic radiation provided at different wavelengths. Thecatheter arrangement can include a drive shaft arrangement which canhold the fiber(s) and can be directly connected to the pullbackarrangement. The drive shaft arrangement can further hold distal optics.The motor(s) can control the pullback arrangement such that the pullbackarrangement can move the catheter and detector arrangements continuouslyat a predetermined speed or a variable speed.

In another exemplary embodiment of the present disclosure is anapparatus for imaging a portion(s) of a biological structure, which caninclude, for example a radiation providing arrangement which can beconfigured to forward a first electromagnetic radiation(s) to thestructure at multiple illumination locations. A detector arrangement canbe is configured to receive a second electromagnetic radiation(s) fromthe multiple locations of the structure. A pullback arrangement which,during the forwarding of the first electromagnetic radiation, can beconfigured to pull back the radiation arrangement(s) of the detectorarrangement. The detector arrangement can be further configured to imagethe portion(s) of the structure based on the second electromagneticradiation(s), without a rotation of the radiation providing arrangement.

In some exemplary embodiments of the present disclosure, the firstelectromagnetic radiation(s) can be forwarded to the structure atmultiple illumination locations substantially simultaneously. The secondelectromagnetic radiation(s) can be received from the multiple locationsof the structure substantially simultaneously. The secondelectromagnetic radiation(s) ca provides information regarding a specklepattern reflected from the portion(s) of the structure. The specklepattern can have an intensity that can vary in time. The variation ofthe intensity of the speckle pattern can provide information regardingmechanical properties of the portion(s) of the structure, which can bedetermined by the detector arrangement. The pullback arrangement can becontrolled by a motor(s). The motor(s) can control the pullbackarrangement to rotate a drive shaft or distal optics.

In another exemplary embodiment of the present disclosure is a methodfor imaging portion(s) of a biological structure, which can include, forexample, using a radiation providing arrangement, forwarding a firstelectromagnetic radiation(s) to the structure at multiple illuminationlocations, using a detector arrangement, receiving a secondelectromagnetic radiation(s) from the multiple locations of thestructure, and pulling back the radiation arrangement(s) of the detectorarrangement. The detector arrangement can be configured to imagesubstantially an entire surface of the portion(s) of the structure basedon the second electromagnetic radiation(s), without a rotation of theradiation providing arrangement.

In some exemplary embodiments of the present disclosure, the firstelectromagnetic radiation(s) can be forwarded to the structure atmultiple illumination locations substantially simultaneously. The secondelectromagnetic(s) radiation can be received from the multiple locationsof the structure substantially simultaneously.

In another embodiment of the present disclosure, a system, method andcomputer-accessible medium can be provided for obtaining informationregarding a biological structure(s), which can include, for example,receiving information related to a radiation(s) reflected from thebiological structure(s) including a speckle pattern(s), and generatingan image of the biological structure(s) based on the information.Pixilation artifacts can be removed from the speckle pattern(s). Aspeckle intensity fluctuation of the speckle pattern(s) can bedetermined by, for example measuring a change of multiple mirror facetsover time. A background fluctuation or a source fluctuation from can beremoved from the speckle pattern(s). Non-fluctuating speckles can befiltered from the speckle pattern(s). A phase fluctuation of thereflected radiation(s) can be determined to, for example, characterizethe tissue.

In another embodiment of the present disclosure, a method of reducinginter-fiber crosstalk in a fiber optic bundle can be provided, which caninclude, for example providing a fiber optic bundle comprising aplurality of core fibers each having a core diameter of 3.0 μm±0.3 μmwith a fluctuation in core diameter of ±0.03 μm to ±0.3 μm, a numericalaperture of at least 0.35, and the fiber optic bundle having a corespacing of 8.0 urn±0.5 μm. Receiving a light into the fiber opticbundle, where the fiber optic bundle has a reduced inter-fibercrosstalk. The diameter of the core fibers can be 3.0 μm±0.2 μm. Thecore fibers can be 3.0 μm±0.1 μm. The fluctuation of the core diametercan be ±0.06 μm to ±0.2 μm. The fluctuation of the core diameter can beapproximately ±0.1 μm. The numerical aperture can be between 0.38 and0.41. The core spacing can be 8.0 μm±0.3 μm. The core spacing can be 8.0μm±0.2 μm. The fiber optic bundle can have an inter-fiber crosstalk thatcan be at least 10% less than the inter-fiber crosstalk within a leachedfiber optic image bundle defined as SCHOTT North America Type 1 at apropagation distance of 0.5 m using 690 nm radiation. The fiber opticbundle can have an inter-fiber crosstalk that can be negligible.

In another exemplary embodiment of the present disclosure is, anapparatus can be provided for laser speckle imaging that has lowinter-fiber crosstalk, which can include, for example a coherentradiation source, a fiber optic bundle configured to receive radiationfrom the coherent radiation source including a plurality of core fibershaving a core diameter, a fluctuation in core diameter, a numericalaperture, and a core spacing, where each of the core diameter, thefluctuation in core diameter, the numerical aperture, and the corespacing can be determined using coupled mode theory (“CMT”). One or moreoptical elements can be configured to direct coherent radiation from thefiber optic bundle to a tissue and collect radiation from the tissue. Adetector can be configured to receive a speckle pattern from the one ormore optical elements.

The diameter of the core fibers can be 3.0 μm±0.3 μm. The diameter ofthe core fibers can be 3.0 μm±0.2 μm. The diameter of the core fiberscan be 3.0 μm±0.1 μm. The fluctuation of the core diameter can be ±0.03μm to ±0.3 μm. The fluctuation of the core diameter can be ±0.05 μm to±0.2 μm. The fluctuation of the core diameter can be approximately ±0.1μm. The numerical aperture can be at least 0.35. The numerical aperturecan be between 0.38 and 0.41. The core spacing can be 8.0 μm±0.5 μm. Thecore spacing can be 8.0 μm±0.3 μm. The core spacing can be 8.0 pm±0.2μm. The fiber optic bundle can include a core diameter of 3.0 pm±0.3 pmwith a fluctuation in core diameter of ±0.1 μm to ±0.3 μm, and anumerical aperture of at least 0.35, and the fiber optic bundle having acore spacing of 8.0 μm±0.5 μm. The numerical aperture and the corespacing can depend on a wavelength of the coherent radiation source. Thecore diameter can depend on the fiber size, the core spacing or thenumerical aperture.

In another exemplary embodiment of the present disclosure, a method canbe provided for tissue analysis, which can include, for exampleilluminating a first cylindrical section(s) of a lumen wall withcoherent or partially coherent light by passing the light through afacet(s) of a multiple-faceted pyramidal mirror, receiving lightreflected from the first cylindrical section of a lumen wall at themirror, illuminating a second cylindrical section(s) of a lumen wallwith coherent or partially coherent light at a time different from thefirst illuminating step by passing the light through a second facet(s)of the multiple-faceted pyramidal mirror, receiving light reflected fromthe second cylindrical section of a lumen wall at the mirror, receivinglight reflected from the mirror at a detector and forming series ofspeckle patterns, and analyzing changes in the speckle patterns at timeintervals sufficient to measure changes caused by microscopic motion ofobjects within the tissue.

According to a still further exemplary embodiments of the presentdisclosure, the illumination can occur by first illuminating cylindricalsection of a lumen wall through either a single facet of the pyramidalmirror at a time, or multiple facets of the pyramidal mirror at onetime, where the facets are not adjacent to each other. The multiplefaceted pyramidal mirror can be a four-sided mirror and the cylindricalsection of a lumen wall can be illuminated through two non-adjacentfacets simultaneously and then the cylindrical section of a lumen wallcan be illuminated through the other two non-adjacent facetssimultaneously. The multiple faceted pyramidal mirror can be a six-sidedmirror and the cylindrical section of a lumen wall is illuminatedthrough two or three non-adjacent facets simultaneously.

These and other objects, features and advantages of the exemplaryembodiments of the present disclosure will become apparent upon readingthe following detailed description of the exemplary embodiments of thepresent disclosure, when taken in conjunction with the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Further objects, features and advantages of the present disclosure willbecome apparent from the following detailed description taken inconjunction with the accompanying Figures showing illustrativeembodiments of the present disclosure, in which:

FIG. 1 is a set of exemplary images of a plaque and a color map of theplaque according to an exemplary embodiment of the present disclosure;

FIG. 2 is an exemplary speckle image according to an exemplaryembodiment of the present disclosure;

FIG. 3 is an exemplary graph illustrating g2(t) curves according to anexemplary embodiment of the present disclosure;

FIG. 4 is an exemplary graph illustrating mean τ for different plaquegroups according to an exemplary embodiment of the present disclosure;

FIG. 5 is an exemplary graph illustrating τ values according to anexemplary embodiment of the present disclosure;

FIG. 6 is an exemplary graph illustrating an estimation of the overallbulk modulus of a necrotic core fibroatheroma as a function of fibrouscap thickness according to an exemplary embodiment of the presentdisclosure;

FIGS. 7A-7C are exemplary graphs illustrating the evaluation of spatialheterogeneity by beam scanning according to an exemplary embodiment ofthe present disclosure;

FIG. 8 is an exemplary colormap illustrating depth imaging in a thin capfibroatheroma according to an exemplary embodiment of the presentdisclosure;

FIG. 9 is an exemplary graph illustrating average plaque 2 measured viaan exemplary leached fiber bundle according to an exemplary embodimentof the present disclosure;

FIG. 10 is an exemplary schematic of an exemplary ILSO catheteraccording to an exemplary embodiment of the present disclosure;

FIG. 11 is an exemplary image of an exemplary LSI catheter sheathaccording to an exemplary embodiment of the present disclosure;

FIG. 12 is an exemplary schematic of an exemplary ILSO procedure in aswine xenograft model according to an exemplary embodiment of thepresent disclosure;

FIGS. 13A and 13B is an exemplary graph illustrating average 2calculated for 3 plaque groups according to an exemplary embodiment ofthe present disclosure;

FIG. 14 is an exemplary graph illustrating 2 calculated in a swine usingexemplary PBO procedures according to an exemplary embodiment of thepresent disclosure;

FIG. 15 is an exemplary schematic of an exemplary motor drive assemblyfor helical scanning according to an exemplary embodiment of the presentdisclosure;

FIGS. 16A and 16B are exemplary images and color maps of 2 over two NCplaques according to an exemplary embodiment of the present disclosure;

FIG. 17A is an exemplary graph illustrating a 3D distribution of meanpenetration depths collected over a catheter according to an exemplaryembodiment of the present disclosure;

FIGS. 17B and 17C are exemplary colormaps illustrating cross-sectionaldistributions along x and y of FIG. 17A according to an exemplaryembodiment of the present disclosure;

FIGS. 18A and 18B are exemplary graphs illustrating spatial resolutionestimated using Monte-Carlo Ray Tracing according to an exemplaryembodiment of the present disclosure;

FIG. 19 is an exemplary OFDI image obtained during visipaque flushingaccording to an exemplary embodiment of the present disclosure;

FIG. 20A is an image of cross section of a leached fiber bundleaccording to an exemplary embodiment of the present disclosure;

FIG. 20B is a schematic of fiber bundle in numerical calculationsaccording to an exemplary embodiment of the present disclosure;

FIG. 21A is an exemplary image illustrating the amplitude of couplingcoefficient x between all the 19×7 modes according to an exemplaryembodiment of the present disclosure;

FIGS. 21B-21F are exemplary graphs illustrating the intensity ofdifferent order modes of central fiber coupled to the correspondingmodes of surround fibers with propagation distance z for 1st, 2nd, 6th,9th and 10th mode respectively according to an exemplary embodiment ofthe present disclosure;

FIGS. 22A-22C are exemplary graphs illustrating core spacing accordingto an exemplary embodiment of the present disclosure;

FIGS. 22D-22I are exemplary graphs illustrating that the couplingstrength can increase as core size increase, core spacing decrease andNA decrease according to an exemplary embodiment of the presentdisclosure;

FIGS. 23A-23I are exemplary graphs and exemplary images illustratingillustrate how speckle pattern change with propagation distance due tocrosstalk between neighboring cores according to an exemplary embodimentof the present disclosure;

FIGS. 24A-24C are exemplary graphs illustrating the reduced change ofintensity in each fiber of optical fiber bundles according to anexemplary embodiment of the present disclosure;

FIGS. 25A-25C are exemplary graphs illustrating that the intensity ineach core of 7 core structure can with propagation according to anexemplary embodiment of the present disclosure;

FIG. 26A is an exemplary image of a small region of an optical fiberbundle cross section according to an exemplary embodiment of the presentdisclosure;

FIGS. 26B and 26C are exemplary recorded raw speckle images and itsFourier transform according to an exemplary embodiment of the presentdisclosure;

FIG. 26D is an exemplary image of a Fourier transformed speckle patternsuperposed by a Butterworth filter according to an exemplary embodimentof the present disclosure;

FIGS. 27A and 27B are an exemplary image and its corresponding exemplarygraph illustrating the notch filter according to an exemplary embodimentof the present disclosure;

FIG. 27C is an exemplary image that utilizes the notch filter of FIG.27B;

FIGS. 28A and 28B are exemplary graphs illustrating the temporalresponse of the total intensity of speckle patterns according to anexemplary embodiment of the present disclosure;

FIG. 29 is an exemplary colormap illustrating the spatially smoothedspeckle pattern average over time according to an exemplary embodimentof the present disclosure;

FIG. 30A is an exemplary image of an exemplary speckle pattern withpixelation artifact removed according to an exemplary embodiment of thepresent disclosure;

FIG. 30B is an exemplary graph illustrating the autocovariance curves ofspeckles within small windows according to an exemplary embodiment ofthe present disclosure;

FIG. 31A is an exemplary image of an acrylamide gel phantom in a 3Dprinted mold according to an exemplary embodiment of the presentdisclosure;

FIGS. 31B-1 and 31B-2 is a set of 8 τ maps of gels A, B, B, and C fromFIG. 31A according to an exemplary embodiment of the present disclosure;

FIG. 31C is an exemplary image of swine aorta with butter injected inbetween the aorta layers according to an exemplary embodiment of thepresent disclosure;

FIG. 31D is a set of the two longitudinal stitched T maps of a tubeaccording to an exemplary embodiment of the present disclosure;

FIGS. 32A-32C shows illustrations of an example of wrapping 2D timeconstant maps onto a cylinder to form a cylindrical view of the timeconstant maps according to an exemplary embodiment of the presentdisclosure;

FIGS. 32D and 32E are exemplary colormaps of a speckle intensity patternand the retrieved phase pattern using the exemplary 2D Hilbert transformaccording to an exemplary embodiment of the present disclosure;

FIG. 32F is an exemplary image illustrating locations of the opticalvortices according to an exemplary embodiment of the present disclosure;

FIG. 32G is an exemplary graph illustrating speckle intensityautocorrelations for two different speckle sequence according to anexemplary embodiment of the present disclosure;

FIG. 32H is an exemplary graph illustrating the locations of the opticalvortex at different speckle frames for the fast varying speckle sequenceaccording to an exemplary embodiment of the present disclosure;

FIG. 32I is an exemplary graph illustrating the locations of the opticalvortex at different speckle frames for the slow varying speckle sequenceaccording to an exemplary embodiment of the present disclosure;

FIGS. 33A-33G are exemplary images of exemplary patterns according to anexemplary embodiment of the present disclosure;

FIG. 34 is an image of an exemplary speckle pattern according to anexemplary embodiment of the present disclosure;

FIG. 35 is an exemplary image of an exemplary colormap according to anexemplary embodiment of the present disclosure;

FIG. 36 is an exemplary schematic illustrating an exemplary mechanismfor the displacement of blood during imaging according to an exemplaryembodiment of the present disclosure;

FIG. 37 is an exemplary image of exemplary M-mode OFDI according to anexemplary embodiment of the present disclosure;

FIGS. 38A-38L are exemplary schematic diagrams of exemplary cathetersaccording to an exemplary embodiment of the present disclosure;

FIGS. 39A-39H are exemplary images of exemplary laser spots according toan exemplary embodiment of the present disclosure; and

FIG. 40 is an illustration of an exemplary block diagram of an exemplarysystem in accordance with certain exemplary embodiments of the presentdisclosure.

Throughout the drawings, the same reference numerals and characters,unless otherwise stated, are used to denote like features, elements,components or portions of the illustrated embodiments. Moreover, whilethe present disclosure will now be described in detail with reference tothe figures, it is done so in connection with the illustrativeembodiments and is not limited by the particular embodiments illustratedin the figures and appended claims.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

One exemplary object of the present disclosure can be to provide, forpatient use, an optical system and method that can be termedIntracoronary Laser Speckle Imaging (“ILSI”), which can evaluate plaqueviscoelastic properties, known to be intimately linked with the risk ofcoronary plaque rupture. It has been determined that plaque rupture canoccur when the atheroma, with severely compromised viscoelasticproperties, can fail to withstand stresses exerted upon it. Therefore,an important ability of an ILSI exemplary system and method, accordingto an exemplary embodiment of the present disclosure, can be to evaluateplaque viscoelasticity, to facilitate an improved understanding ofplaque stability, and advance clinical capability for the detection ofvulnerable plaques with the highest risk of rupture in patients.

The exemplary ILSI technology, according to an exemplary embodiment ofthe present disclosure, can be based on an exemplary laser speckleapproach. For example, laser speckle, a grainy pattern formed by theinterference of laser light scattered from tissue, can be dynamicallymodulated by endogenous particular Brownian motion governed by themechanical susceptibility of tissue. It has been previously demonstratedthat the time scale of speckle modulations, defined by the speckledecorrelation time constant, can provide a highly sensitive metric ofviscoelasticity that can be closely related with plaque composition andmechanical moduli. Given the potential impact of ILSI in measuring a keymechanical metric of plaque stability, it can be possible to utilize theexemplary ILSI systems and methods for evaluating coronary plaques inpatients. The large size (e.g., approximately 1.5 mm), and limited pointsampling capability of existing ILSI devices, however, can render itless than optimal for human use. Therefore, it can be possible toprovide a miniaturized ILSI catheter for human use which can facilitatescanning of the entire circumference and length of the coronary arteryto evaluate maps of arterial viscoelasticity distribution.

Exemplary Object 1: Provide ILSI Catheter and Console Suitable for HumanUse

The exemplary ILSI technology can utilize a miniaturized intracoronarycatheter (e.g., <1.0 mm) to acquire speckle images from the arterialwall. The catheter can be interfaced with a high-speed console tofacilitate helical scanning of the coronary artery. Speckle analysis andvisualization procedures can be implemented to reconstruct cylindricalmaps of arterial time constants over the circumference and length ofcoronary segments. Performance benchmarks including catheter size andmechanical characteristics, imaging time and spatial resolution can beoptimized and verified in human cadaveric hearts. The exemplary ILSIcatheter performance can be evaluated in living swine using a human toswine coronary graft model to facilitate imaging of human coronariesunder physiologic conditions.

Exemplary Object 2: Indicate Safety and Feasibility of ILSI Technologyin Patients

Regulatory procedures involving catheter evaluation, biocompatibilitytesting, laser exposure evaluation and safety studies in living swinecan be performed in preparation for hospital IRB and FDA applications toconduct clinical studies. ISO 10555 requirements can be followed tofabricate sterile, single-use catheters in a controlled, Class 10000 GLPclean room facility at the Wellman Center. Following regulatoryapproval, ILSI can be conducted in 20 patients undergoing percutaneouscoronary intervention. Cylindrical maps of arterial mechanicalproperties measured by ILSI can be registered and correlated withmicrostructural information obtained using intracoronary OFDI.

The exemplary ILSI can provide a tool to significantly advance currentscientific understanding of vulnerable plaque instability in patients.It can also provide a powerful diagnostic role within a comprehensiveclinical paradigm of AMI management to facilitate an identification ofplaques with the highest risk of rupture for treatment prior to adverseevents in patients.

Exemplary Strategy

Exemplary Vulnerable Plaque Detection:

AMI, frequently caused by the rupture of vulnerable coronary plaque,claims more lives worldwide than cancer, accidents and AIDS combined.Autopsy studies reveal a type of plaque, the thin cap fiutopsy stud(“TCFA”) implicated at the site of culprit thrombi in >70% of patientswho have succumbed to AMI. (see, e.g., References 1 and 2). TCFA's canbe most frequently found within the proximal approximately 5 cm of themajor coronary arteries and can be histologically hallmarked by thepresence of a thin fibrous cap (e.g., <65 μm), rich in macrophages,overlying a large necrotic lipid pool. (See, e.g., References 1-5). Anumber of technologies such as optical coherence tomography (“OCT”),virtual histology intravascular ultrasound (“VH-IVUS”), computedtomography (“CT”), angioscopy and near infrared spectroscopy (“NIRS”)have been investigated in patients to evaluate key morphologic featuressuch as fibrous cap thickness, plaque burden, calcific nodules and lipidcontent. (See, e.g., References 6-26) An important challenge, however,in identifying plaques with the highest risk of rupture in patients canbe that plaques with similar vulnerable morphologic features do not allpossess an equal likelihood of rupture. For example, in 70% of patientsdying from AMI, multiple TCFA's can be found without rupture at sitesremote from the culprit plaque and in non-culprit arteries, (see, e.g.,Reference 2) and can appear with similar frequency in stable patientswith asymptomatic coronary artery disease (“CAD”). (See, e.g.,References 2, 27-29). Moreover, in approximately 20% of cases, plaquerupture can be observed in necrotic core (“NC”) lesions with thickerfibrous caps (e.g., >100 μm), intra-plaque hemorrhage or calcificnodules. (See, e.g., References 2, 28, 30-31). These findings call intoquestion the current detection paradigm that relies entirely onmorphologic criteria, and highlights, the need to augment morphologicfindings with important surrogate metrics, such as mechanical metrics,in order to accurately evaluate the risk of plaque rupture. (See, e.g.,References 1 and 2).

Knowledge of mechanical metrics can be important to accurately determinethe risk of plaque rupture. The atheroma can be viscoelastic in nature,exhibiting both liquid (e.g., viscous) and solid (e.g., elastic)behavior. During the pathogenesis of atherosclerosis, from lesioninitiation to rupture, the viscoelastic properties of the plaque can bealtered by a complex milieu of hemodynamic and biochemical processes.The ultimate event of plaque rupture can be a biomechanical failure thatcan occur when a plaque with severely compromised mechanical propertiescan be unable to withstand loads exerted on it. (see, e.g., References32-41). Therefore, in order to identify plaques with the highest risk ofrupture, it can be important to complement morphologic informationprovided by current technologies with knowledge of viscoelasticproperties.

Current knowledge of plaque viscoelasticity however can be limited as itcan largely be derived from ex vivo mechanical testing of cadaveric andanimal arteries. These measurements can provide only a retrospectivesnapshot of bulk properties, limiting the understanding of howmechanical metrics can be altered during the plaque remodeling in vivo.Therefore, important estimates of plaque viscoelastic propertiespredisposed to the final event of rupture can be currently unknown.Crucial questions remain on how current knowledge of plaque mechanicalstability translates in vivo, restricting the opportunity for accuratedetection of high-risk vulnerable plaques in patients. Together, thesefactors can highlight a important barrier in the field: the ability todetect plaques with the highest risk of rupture can be significantlyhindered by the absence of tools for the mechanical characterization ofcoronary plaques in patients.

An exemplary embodiment of an ILSI system and method according to thepresent disclosure can be provided for a clinical use that can be usedto evaluate the viscoelastic characteristics of coronary plaques inpatients. The exemplary ILSI systems and methods can measures plaqueviscoelasticity by utilizing an exemplary laser speckle approachdeveloped in a laboratory, which can interrogate the ensemble Brownianmotion dynamics of light scattering particles intimately linked with themicromechanical behavior of the atheroma. The exemplary ILSI systems andmethods can measure an index of viscoelasticity defined by the speckledecorrelation time constant (τ) that can be highly sensitive to minutealterations in the viscoelastic properties of the atheroma (e.g.,Section C). (See, e.g., References 42-46). The exemplary ILSI systemsand methods can provide an improved understanding of human CAD andadvance clinical capability to detect plaques with the highest risk ofrupture in patients as discussed below.

Exemplary Understanding of CAD by ILSI:

The exemplary ILSI technology can provide important mechanical metricsimplicated in plaque instability in animals and patients. Theminiaturized ILSI catheter (e.g., <1 mm) can facilitate evaluation ofsmall coronary vessels and flow limiting lesions. The reconstruction of2D maps (e.g., FIG. 1) can provide knowledge of viscoelasticitydistributions over the circumference and length of the coronary vessel.The capability to evaluate depth-resolved 3D information at high spatialresolutions (e.g., approximately 100 μm) can be provided to facilitatean important understanding of the mechanical properties of the lipidpool and fibrous cap in NC plaques of highest clinical relevance. Thesuperior sensitivity of the exemplary ILSI systems and methods describedherein to minute alterations in viscoelasticity can be utilized forplaque remodeling during the natural history of coronary atherosclerosisleading to rupture. It can be known that in early lesions, inflammatoryprocesses can influence the accumulation of low viscosity lipid. (See,e.g., References 47 and 48). In advanced plaques, apoptosis of foamcells and intraplaque hemorrhage can result in large necrotic lipidpools of further reduced viscosity. (See, e.g., References 49 and 50).Furthermore, lipid pool viscosity can also be influenced by cholesterol,phospholipids and triglyceride content. (See, e.g., Reference 50). ILSImeasurements of lipid pool viscosity can provide insights on the loadbearing properties of the atheroma, and can offer a likely explanationfor why TCFAs do not all possess the equal likelihood of rupture. Themechanical properties and morphology of the fibrous cap can be radicallyaltered by a net reduction in collagen content that can occur due to animbalance in collagen proteolysis by matrix metalloproteinases (“MMP”)and synthesis due to apoptosis of smooth muscle cells. (See, e.g.,References 51-53). ILSI can provide knowledge of important estimates offibrous cap viscoelasticity related with the final event of plaquerupture.

Finite element (“FE”) studies of coronary cross-sections derived fromhistology sections, or IVUS and OCT images can show that peak stressesassociated with plaque rupture can be dependent on the geometry andviscoelastic properties of the fibrous cap and lipid pool, and plaquerupture can become imminent when the peak stress in the plaque surpassesan important amplitude. (See, e.g., References 32-41, 54 and 55).Precise measurement of peak stress amplitudes predisposed to ruptureneeds accurate estimates of the viscoelastic properties of plaquecomponents in situ. ILSI can help address this challenge; combining FEAapproaches with ILSI maps of viscoelasticity distributions can provide apowerful new method for accurate evaluation of peak stress in situ.

The spontaneous rupture of coronary plaques leading to AMI can be uniquein human CAD. Because there can be no realistic animal models availablethat can mimic this event under physiologic conditions, many keyhypotheses that relate mechanical metrics with the final event of plaquerupture can only be best studied in human patients. Exemplaryembodiments of the present disclosure address this challenge byproviding translating ILSI for use in patients.

The exemplary ILSI systems and methods can be used for the detection ofvulnerable plaques in patients at risk for AMI. Recent clinical studiesshow that 10% of patients undergoing PCI and statin therapy followingthe first acute event develop a second adverse event due to plaquerupture within 3 years. (See, e.g., References 56 and 57). The exemplaryILSI systems and methods can be used by interventional cardiologists todetect potential plaques such that a second major adverse event can beprevented. Thus, over 100,000 people annually in the USA alone canbenefit by ILSI screening.

In order to reduce mortality due to AMI in the general population, newpreventative paradigms for AMI management can be realized. Theseexemplary paradigms can use a comprehensive screening strategy toidentify at risk patients and detect high-risk vulnerable plaques inthese patients such that they can be treated prior to AMI. Non-invasiveimaging of the coronary tree using computed tomography (“CT”) andmagnetic resonance imaging (“MM”) approaches can be important inidentifying asymptomatic patients at highest risk of AMI. (See, e.g.,References 58 and 59). These approaches, however, lack sufficientsensitivity and resolution to evaluate mechanical and morphologicalcharacteristics to detect vulnerable coronary plaques. A second level ofintracoronary screening using ILSI can be used to evaluate plaques withcompromised mechanical stability likely to cause AMI in asymptomaticpatients at risk.

Furthermore, the exemplary ILSI systems and methods elegantly can beused for an integration with other intracoronary technologies such asoptical coherence tomography (“OCT”) and optical frequency domainimaging (“OFDI”) or intravascular ultrasound (“IVUS”), (see, e.g.,References 60-62)(see, e.g., Reference 57) to render powerful approachesthat can place mechanical findings within a morphologic context for acomposite evaluation of plaque stability.

Further, treatments for stabilization, including low forceself-expanding and bio-absorbable stents, vascular tissue implants, stemcell and photodynamic therapy, can be developed by a number of companiesand groups. These therapeutic interventions can utilize diagnostic toolsfor the accurate diagnosis or determination of rupture-prone coronaryplaques prior to treatment.

Brief Description of Exemplary ILSI Systems and Methods

It can be important to provide a tool to evaluate the viscoelasticproperties of coronary plaques in patients. IVUS-based elastography hasbeen developed to measure plaque strains in response to intra-luminalstress. However, evaluation of plaque viscoelastic properties can beintractable using this approach. (See, e.g., References 63 and 64).While recent studies have utilized inverse methods and deformable curvesto reconstruct Young's moduli from elastography strain maps, theapproximation of linear elastic behavior by these methods can restrictaccurate evaluation of the load bearing properties of viscoelastictissue components and low viscosity lipid pools. It can be possible toapply elastography approaches to OCT to provide higher resolution forstrain estimation relative to IVUS. Loss of OCT signal in lipid richtissue, however, can preclude strain assessment in NC plaques, thussignificantly limiting clinical utility.65-67 There are no knowntechniques that can evaluate the viscoelastic properties of coronaryplaques in patients.

The following benefits can be provided by the exemplary ILSI systems andmethods: 1) a measurement of plaque viscoelasticity that cannot beaccomplished by any other previously known technique. 2) facilitation ofa clinical grade ILSI device for use in patients. 3) The use of theexemplary ILSI device in human translation.

The exemplary ILSI device can facilitate a comprehensive screening ofthe arterial circumference over long coronary segments to evaluateplaque viscoelasticity maps at spatial resolution approximately 100 μm.It can be possible to provide an exemplary miniaturized ILSI catheter(e.g., 2.4-3.0 F) including one or more low cross-talk fiber bundleswith sufficient motion tolerance to evaluate the coronary wall in vivo.To achieve capability for helical scanning, it can be possible toprovide an exemplary optical rotary junction and motor drive assemblythat can couple and receive light from multiples cores of the fiberbundle while simultaneously rotating and translating the catheter duringimaging. In order to facilitate a collection of arterial speckledecorrelation information, a programmable stepper motor can be utilizedto encode and transmit torque to the catheter in discrete increments,which can facilitate sufficient sampling of the coronary circumferenceat a rotational rate of approximately 1 Hz. The exemplary ILSI devicecan utilize a high-speed complementary metal oxide semiconductor(“CMOS”) camera (e.g., 2 kHz frame rate) to obtain r measurements oververy short time scales (e.g., 25 ms) over which the influence of lowfrequency arterial deformations induced by cardiac (approximately 1 Hz)or respiratory (approximately 0.2 Hz) motion can be largely mitigated.Using this exemplary approach, ILSI measurements can be accomplishedwithout the need for electrocardiogram (“EKG”) gating in vivo.

The exemplary ILSI device does not need apriori approximations on plaquegeometry or loading conditions to measure viscoelasticity, therefore,automated ILSI analysis can be rapidly accomplished rendering ease ofuse in the catheterization suite. Cylindrical 2D maps of plaqueviscoelasticity can be provided from ILSI data to measure the influenceof spatial heterogeneities. Exemplary methods can be provided that canutilize a spatio-temporal speckle analysis in conjunction with MonteCarlo models of light propagation to provide a new technique fordepth-resolved ILSI in NC plaques in vivo. By combining circumferentialscanning with depth-resolved ILSI, the complete 3D determination ofplaque viscoelasticity distributions can be achieved at selected sitesto furnish information on the load bearing properties of the lipid-pooland fibrous cap. Because ILSI measurements can be based on phase shiftsof multiply scattered light caused by minute scatterer displacements,this exemplary technique can be highly sensitive to small changes inplaque viscoelastic properties, and can render high precision for theevaluation of lipid pools.

It can also be possible to provide a clinical translation of the ILSItechnology according to an exemplary embodiment of the presentdisclosure.

Exemplary Approach

Exemplary Overview of Approach:

ILSI can be based on an exemplary laser speckle approach that has beendeveloped to evaluate the viscoelastic properties of tissue. (See, e.g.,References 42-45, 65 and 68-70). For example, laser speckle (e.g., FIG.2), (see, e.g., Reference 71) a grainy intensity pattern that occurs bythe interference of coherent light scattered from tissue, can bemodulated by the Brownian motions of endogenous particles within tissue.In can be well known that the extent of particular Brownian motion canbe intimately related with the micromechanical susceptibility of themedium, and particles can exhibit larger motions when their localenvironment can be less viscous. (See, e.g., References 72-74).Consequently, in an atheroma due to the low viscosity of lipid,scatterers can exhibit rapid Brownian motions, eliciting rapid speckleintensity fluctuations compared to stiffer fibrous regions. The extentof speckle fluctuations can be quantified from the speckle decorrelationcurve, g2(t), which can be obtained by calculating the normalizedcross-correlation coefficient over a time series of laser specklepatterns (e.g., FIG. 3). The rate of speckle modulation given by thespeckle decorrelation time constant, r can provide a highly preciseindex of plaque viscoelasticity that can be closely related to plaquecomposition and viscoelastic moduli. (See, e.g., References 42, 46)

(i) Plaque Characterization:

Studies have been conducted to demonstrate the capability of LSI forevaluating the index of viscoelasticity, τ, in cadaveric plaques.⁴²Time-varying speckle patterns were obtained from approximately 100arterial samples using a Helium Neon source (e.g., 632 nm) and a CMOScamera to evaluate g2(t). The time constant, r was measured byexponential fitting of g2(t) for each plaque (e.g., FIG. 4). Exemplaryresults show that τ can provide highly sensitive discrimination ofplaque type (e.g., p<0.001). In particular, LSI can demonstrateexquisite sensitivity (e.g., 100%) and specificity (e.g., 92%) fordiscriminating the viscoelastic properties of TCFAs (e.g., τ=45 ms) dueto rapid particular Brownian motion within low viscosity lipid pool(e.g., p<0.0001). Similarly, stiffer fibrous and fibrocalcific lesionscan elicit significantly larger τ values (e.g., p<0.001).

(ii) Exemplary Relationship Between τ and Plaque Composition:

Since viscoelastic properties can be highly dependent on composition, τshowed high correlation with plaque collagen content (e.g., R=0.73;p<0.0001) and consequently with cap thickness (e.g., R=0.87; p<0.001).(See, e.g., Reference 42). Given the low viscosity of lipid, a strongnegative correlation (e.g., R=−0.81; p<0.0001) between ti and lipidcontent was observed. These exemplary results demonstrate that LSI canmeasure an index of viscoelasticity, t, closely related withcompositional metrics associated with plaque stability.

(iii) τ and Viscoelastic Modulus:

In order to demonstrate the potential of LSI in estimating theviscoelastic properties of samples, the relationship has been evaluatedbetween the modulus of viscoelasticity, G, measured by mechanicaltesting and LSI time constant, r, using (a) homogenous gels, and (b)atherosclerotic plaques. In the present disclosure, the term, ‘bulk’modulus, G, can be used to define the overall modulus which integratesover the sample volume.

(a) Homogenous Gels:

LSI was performed on collagen, PDMS, PEG and Matrigel substrates ofvarying concentrations. Corresponding mechanical testing measurementswere performed on all samples using a strain-controlled rheometer (e.g.,ARG2, TA Instruments Inc., MA) to measure modulus G. The samples wereloaded between the parallel plates of the rheometer and an oscillatorystrain (e.g., 1%) was applied over a frequency range of about 0.1-5 Hz.High correlation between τ and G (e.g., R=0.92, p<0.001) was observedover the linear frequency range in all samples. These results confirmthat τ can provide a highly accurate estimate of sample viscoelasticproperties (e.g., FIG. 5). To evaluate the measurement sensitivity ofLSI, time lapse measurements of τ were compared with G values measuredduring slow curing of PDMS gels over 24 hours. High correspondencebetween τ and G was observed (e.g., R=0.95, p<0.01), confirming the highsensitivity of the LSI approach to changes in viscoelastic properties ofthe sample.⁷⁵

(b) Arterial Plaque Studies:

LSI was conducted by averaging τ values over 3 mm disks of aortic sites,histologically confirmed as calcific, fibrous and lipid-rich. Mechanicaltesting was performed as above, which revealed distinct G values betweenplaque groups: 2.27×10⁵ Pa (calcific), 3.65×10³ Pa (fibrous) and2.23×10³ Pa (NCFA). Analysis of variance (“ANOVA”) tests showedstatistically significant differences in G for the plaque types (e.g.,p<0.001). These values also correspond with previously publishedreports. (See, e.g., Reference 76). For all plaques, τ correlated wellwith G (R=0.97, p<0.001), establishing the close relationship between τand plaques viscoelastic properties, and suggesting that τ can provide akey metric related to the mechanical strength of the plaque.

Exemplary Influence of Spatial Heterogeneities:

(i) Modeling Studies:

To evaluate the influence of structural parameters on the bulk modulus,a plaque was modeled as a multilayered cylinder of thickness, L andviscoelastic modulus, G. For the purpose of this model, it can beassumed that viscoelastic modulus, G≈G′ (elastic modulus), supported byprevious reports. (See, e.g., References 76 and 77). Given its clinicalsignificance, it can be possible to consider a NC plaque with a fibrouscap and NC of thicknesses L1 and L2, and moduli G1 and G2, loadedbetween the parallel plates of a rheometer. The twisting moment Mapplied by the rheometer can be determined by the distribution of shearstresses integrated across the plaque. (See, e.g., Reference 50). Byequating M with the polar moment of inertia and the angular displacementof the sample, it can be possible to deduce the expression, for example:

$\begin{matrix}{G = \frac{{LG}_{1}G_{2}}{{L_{1}G_{2}} + {L_{2}G_{1}}}} & (1)\end{matrix}$

Eqn. (1) shows that the overall bulk modulus of the plaque can berelated to the thickness and viscoelastic modulus of each layer. Eqn.(2) below can be applied to evaluate the relationship between the bulkmodulus G and fibrous cap thickness in a NC plaque, using previouslyreported values (see, e.g., Reference 76) of G1=496 kPa, and G2=222 kPa,for fibrous and lipid rich tissue and can evaluate the influence ofvarying fibrous cap thickness (e.g., 0-500 μm) on bulk G (e.g., FIG. 3).This exemplary model can be also extended to include multiple layers ofvarying depth-dependent viscoelasticity by using the following exemplarygeneralized equation:

$\begin{matrix}{\frac{L}{G} = {\sum\limits_{n}\frac{L_{i}}{G_{i}}}} & (2)\end{matrix}$

These studies indicate that the fibrous cap thickness can greatlyinfluences the overall bulk viscoelasticity of the plaque (e.g., FIG.6), and also indicate that the measurement of bulk viscoelasticproperties can provide a key metric closely related with plaquestability.

(ii) Lateral Scanning in LSI:

To evaluate the capability of LSI in measuring heterogeneities, laserspeckle images of plaques were obtained by scanning the He Ne spot at300 μm increments and the spatial distribution of τ was measured. FIG. 7demonstrates the lateral variation of τ as a function of beam location.As the beam was scanned across each lesion, τ varied significantlydepending on tissue type: τ was low (e.g., 20-50 ms) in the lowviscosity NC regions (e.g., FIG. 7A) and higher in the stiffer calcific(e.g., approximately 2200 ms in FIG. 7B) and fibrous (e.g.,approximately 800 ms in FIG. 7C) regions. Similarly 2D maps of thespatial ti distributions were obtained by beam scanning over the regionof interest (“ROI”) (e.g., FIG. 1), to facilitate a detection ofheterogeneities such as calcific nodules and lipid pools to facilitatecomprehensive coronary screening.

(iii) Depth-Dependent Heterogeneities:

Due to the diffusive properties of light propagation in tissue, photonsreturning from deeper regions have a higher probability of remittancefarther away from the illumination location:⁷⁸⁻⁸¹ In such publications,τ was computed over the entire speckle pattern. Therefore, Brownianmotion was integrated over all optical depths and information abouttissue heterogeneity was lost. By combining LSI with an exemplary MonteCarlo analysis of light propagation, depth information can be obtained.(See, e.g., Reference 43). In this study, the capability to measurefibrous cap thickness was demonstrated by analyzing variation in τ as afunction of radial distance, ρ, from the illumination location in eachspeckle image. Fibrous cap thickness estimates obtained using thismethod, were highly correlated with Histologic measurements (e.g., FIG.8). These findings indicate the potential of obtaining depth informationusing LSI, which can be further explored for in vivo intracoronary usein the current proposal.

Exemplary Intracoronary ILSI

Exemplary ILSI catheter construction and testing

(i) Fiber Bundle Selection:

Optical fiber bundles form an important part of the exemplary ILSIcatheter to transmit speckle patterns. One challenge can be that specklemodulation can be influenced by inter-fiber light leakage (e.g.,cross-talk) which can likely be exacerbated during motion. A study⁴⁴ wasperformed to investigate the influence of motion on the diagnosticefficacy of fiber bundle based LSI in 75 arterial plaques, whilecyclically modulating the flexible length of the bundle to mimic cardiacmotion and tortuosity. A variety of fiber bundles were tested. Thebundle with the highest motion tolerance was selected as having the (a)highest correlation, (b) lowest error, and (c) minimal statisticallysignificant difference in measuring plaque ti values under stationaryand moving conditions. Low cross-talk leached fiber bundles provided thebest motion stability (e.g., SCHOTT, Inc.), likely due to themanufacturing (e.g., leaching) process which can result in largeseparations between fiber cores and reduced cross-talk. (See, e.g.,Reference 44). In particular, the leached bundle with the smallestpartial core size of approximately 0.36 (e.g., core area÷fiber area)provided the best results for the above three criteria (e.g., FIG. 9).Based on these findings, miniaturized leached fiber bundles with lowpartial core sizes (e.g., <0.4) can be incorporated in theclinical-grade ILSI catheter proposed in this grant.

(ii) Exemplary ILSI Catheter:

An exemplary ILSI catheter (e.g., dia=1.57 mm) can be provided that caninclude an inner optical core and custom-designed external sheath.⁴⁶ Theoptical core (e.g., FIG. 10) can consist of an optical fiber toilluminate the arterial wall and a leached optical fiber bundle tocollect arterial speckle patterns. The exemplary design of the catheterdistal optics for light delivery and speckle image transmission wasoptimized using ZEMAX (e.g., ZEMAX Development Corporation) for anapproximate 500 μm field of view (“FOV”). The optical elements (e.g.,GRIN lens, polarizer and mirror) were assembled at the distal face ofthe fiber bundle within a clear tube (e.g., FIG. 10) and the proximalbundle face was imaged via an objective lens and CMOS camera. To housethe optical core, it can be possible to use a double-lumen cathetersheath (e.g., FIG. 11). Since blood presents an impediment tointracoronary optical approaches, the sheath can include an occlusionballoon which can facilitate the comparison of the effectiveness ofproximal balloon occlusion (“PBO”) with flushing techniques during theexemplary ILSI procedure. The sheath can also have radio-opaque markerat the distal end for fluoroscopic guidance and a rapid exchangeguidewire port. The catheter performance in evaluating cadaveric plaqueswas compared with free-space LSI: high correlation (e.g., R=0.79,p<0.01) was attained between ILSI and free space τ measurements. For invivo testing, the catheter was interfaced with a portable console forintravascular evaluation in the aorta of a living rabbit. Distinctdifferences in arterial τ measured at normal aortic and stented sitesconfirmed in vivo feasibility. (See e.g., Reference 46).

Exemplary Feasibility of Intracoronary LSI in Living Swine

The feasibility of ILSI has been reviewed for coronary evaluation invivo, and to determine the influence of cardiac motion, and blooddisplacement approaches.

(i) Human to Swine Coronary Xenograft Model:

Exemplary choice of animal model can be motivated by two keyrequirements: (1) feasibility of ILSI can be best tested on humancoronary disease, and (2) testing must be performed under conditionsthat mimic human cardiac physiology. This model has been previouslydescribed to test intracoronary optical technologies. (See, e.g.,References 82 and 83). Cadaveric hearts (e.g., N=3) from patients whodied of AMI were obtained (e.g., NDRI). LAD and RCA coronaries (e.g.,proximal 5 cm) were prosecuted and side branches ligated. Coronarygrafts were marked with India ink on the adventitial side to identifydiscrete sites for co-registration with Histopathology. In anesthetizedswine (e.g., N=3), the chest was opened, the grafts were sutured on thebeating swine heart, and blood flow was redirected through the graft viaan aorto-atrial conduit. A total of 24 discrete sites in 6 grafts wereevaluated using ILSI in 3 living swine.

(ii) Exemplary ILSI Procedure:

A portable console was developed, which incorporated a Helium-Neonsource (e.g., 632 nm, 30 mW) and a CMOS camera to capture speckle imagesat frame rate approximately 1 kHz (e.g., 512×512 pixels). The ILSIcatheter was manually advanced under fluoroscopic guidance over a guidewire via the left carotid and to each discrete lesion by co-registeringthe illumination spot with the visible India ink mark on the artery.Prior to imaging, the proximal occlusion balloon was engaged whileflushing with Lactated Ringers (“LR”) to ensure that blood did notre-enter the FOV. To evaluate the influence of cardiac motion,acquisition of the first speckle image was triggered on the R-wave ofthe swine EKG signal, followed by asynchronous acquisition of subsequentframes over approximately 5 cardiac cycles. Following the exemplary ILSIprocedure, the swine were sacrificed, and the grafts explanted andprocessed for Histopathological evaluation. Plaques (e.g., N=24) werediagnosed as lipid pool (e.g., n=3), pathological intimal thickening(“PIT”) (e.g., n=7) and fibrous (e.g., n=14) plaques. (See, e.g.,Reference 1). ILSI analysis was performed as detailed below.

(iii) Influence of Cardiac Motion:

In order to achieve clinical viability in patients, the ILSI technologycan facilitate rapid coronary screening while retaining adequate motionstability over the cardiac cycle. While EKG gating can be implemented tomitigate the influence of cardiac motion, this approach can addsignificant time to the imaging procedure. Instead, a non-gated approachcan permit rapid imaging of long coronary segments facilitating the useof the ILSI device in patients. The studies below were performed toinvestigate the influence of cardiac motion and compare EKG-gated versusnon-gated ILSI measurements.

To evaluate the EKG gating approach to conduct ILSI, the ti value foreach plaque was calculated at the mid-diastole phase of the cardiaccycle (e.g., approximately 600 ms after onset of R-wave). To evaluatethe non-gated approach, the ti value for each plaque was computed at atime point during the cardiac cycle that was randomly selected bysoftware. For both cases, τ was calculated by exponential fitting of 50ms of the initial decorrelation of the g2(t) curve. FIG. 13A shows anexemplary illustration of the average τ computed for the plaque groupsusing the EKG-gated and non-gated approaches, and the results of thepairwise comparisons between plaque groups are shown in FIG. 13B. Usingboth approaches, differences in τ between the three plaque groups werehighly significant. Demonstrating that plaque viscoelasticity could bewell distinguished even under conditions of cardiac motion. This can bebecause sufficient motion stability can be achieved by employing rapidimage acquisition rates (e.g., ≥1 kHz) using a high speed CMOS detectorto measure laser speckle fluctuations over very short time scales. Invivo plaque time constants were about <25 ms (e.g., FIG. 13), indicatingthat imaging durations of about 25 ms can sufficiently enable plaquediscrimination. Given the low frequency of cardiac motion (e.g.,approximately 1 Hz) relative to the high rate of speckle decorrelationover short time scales, ILSI can be conducted during the cardiac cyclewithout the need for EKG gating. A key result can be that differences inτ measured within the same plaque group using the two exemplaryapproaches were not significantly different (e.g., FIG. 13A). This candemonstrate that non-gated ILSI works just as well as EKG-gated ILSI invivo. From the results of this study, it can be possible to infer that:(a) an imaging duration <25 ms can be sufficient to measure speckledecorrelation for plaque evaluation in vivo, and (b) ILSI can beconducted in vivo without EKG-gating.

(iv) Intracoronary Flushing:

Similar to other intravascular optical techniques, in ILSI the presenceof blood can hinder imaging. Proximal balloon occlusion (“PBO”) andpurging with flushing media can be two exemplary methods routinely usedin conjunction with angioscopy and OCT to displace blood during theimaging procedure. (See, e.g., References 19 and 61). While PBO canroutinely be employed in Japan, the risk of ST-segment elevation canlimit the widespread adoption of this method in the USA. Instead,flushing with contrast agent (e.g., Visipaque) or Lactated Ringers(“LR”) solution can routinely be used as a safe alternative duringimaging.′ Therefore, in order to assess feasibility of ILSI for patientuse, studies were conducted in native coronaries of living swine tocompare PBO and flushing approaches as detailed below.

(a) Balloon Occlusion Versus Flushing in Living Swine:

A 3 mm coronary stent was deployed into the native LAD of anesthetizedswine, and ILSI was conducted at normal arterial sites, and within thestent, while the proximal occlusion balloon was engaged. The balloon wasthen disengaged, and the sites were evaluated in conjunction with a 30cc Visipaque flush. Using both PBO and flushing approaches, differencesinti between the normal unstented and stented sites were highlysignificant (e.g., p<0.01), demonstrating that ILSI can be conductedusing either of the two exemplary approaches to displace blood duringimaging. In addition, differences inti measured within the same locationwith both PBO and flushing were not significantly different (e.g., FIG.14). This can demonstrate that ILSI can be conducted in conjunction withflushing to sufficiently displace blood during imaging.

(b) Influence of Residual Blood:

To test the influence of residual blood cells on τ values, it can bepossible to perform LSI on four aortic plaques within a flow cellthrough a 3 mm intervening layer of whole blood (e.g., HCT=30%),serially diluted using PBS. For example, 2 values at HCT<0.1% weresimilar to those values measured without any intervening medium.Subsequently OCT imaging was performed and it was determined that atHCT >0.03%, backscattering from blood cells was clearly evident in OCTimages. In clinical studies using intracoronary OCT and recent swinestudies (e.g., FIG. 19) no backscattering from blood cells can beobserved during flushing. Since blood does not affect LSI at a HCT<0.1%and purging in patients can apparently reduce the intracoronary HCT to<0.03%, levels of residual blood cells during flushing can besufficiently low to conduct ILSI.

Summary of Exemplary Studies:

Through certain studies, the exemplary LSI systems and methods have beendeveloped and validated as a powerful tool to evaluate plaqueviscoelastic properties. These exemplary studies have demonstrated, 1)The LSI time constant, τ, can provide a metric that can intimately belinked with plaque viscoelastic properties, 2) LSI can enable highlyprecise differentiation of plaque type, and can have exquisitesensitivity for the evaluation of TCFAs. 3) LSI can facilitate themeasurement of spatial and depth-dependent heterogeneities, 4)Intracoronary LSI can be conducted in vivo at high imaging rates inconjunction with flushing. Given the high clinical impact of measuringcoronary plaque viscoelasticity and supported by the success ofexemplary results in the current disclosure, it can be possible toextend LSI for intracoronary evaluation in patients. It can also bepossible to provide, according to an exemplary embodiment of the presentdisclosure, clinical grade ILSI technology, and conduct the first inhuman feasibility studies as detailed below.

Exemplary Design and Methods

Overview of Exemplary Design:

Efforts have been directed towards developing clinical-grade ILSIcatheters suitable for human use and a console to enable helicalscanning over long coronary segments. Preclinical validation of the newILSI device can be conducted to evaluate coronary plaque viscoelasticityin living swine. Further, for human clinical studies can be conducted,for example, in 20 patients to assess the safety and utility of ILSI. Itcan also be possible to obtain an exemplary tool that can improve anunderstanding of human CAD.

Exemplary Methods:

The exemplary ILSI catheter described in exemplary studies above enabledthe demonstration of in vivo feasibility for intracoronary evaluation.Its functionality for patient use, however, can be restricted given itslarge size (e.g., approximately 4.5 F/1.57 mm). In addition, theexisting ILSI devices may only be permit limited point sampling ofdiscrete sites, therefore precluding the capability for comprehensiveintracoronary screening to evaluate arterial viscoelasticitydistributions. Furthermore, because the exemplary device can utilizeillumination over an extended beam (e.g., approximately 250 μm), and theindex of viscoelasticity, 2, evaluated over the entire speckle pattern,depth-dependent information can be lost or degraded. These issues can besolved according to certain exemplary embodiments described hereinbelow.

In order to achieve clinical utility, for example, a miniaturizedexemplary ILSI catheter (e.g., approximately 2.4 F-3.0 F/0.8-1.0 mm) canbe provided that can access small flow-limiting coronary arteries ofpatients, and can conduct rapid helical scanning of coronary segments.Speckle analysis and visualization methods can be implemented toreconstruct arterial viscoelasticity distributions. This can facilitatecomprehensive circumferential screening of about 3.0-5.0 cm of the majorcoronary arteries with a longitudinal image spacing (e.g., pitch) ofabout 0.25-1.0 mm, while administering a safe total amount (e.g., <100cc) of flushing media.

Exemplary ILSI Device:

Exemplary modifications of the exemplary device can be focused oncertain components thereof, for example: (i) catheter, (ii) motor driveassembly for helical scanning, and (iii) console. The catheter caninclude an inner cable that can house the optical core. During imaging,the motor drive assembly can rotate and simultaneously pullback theinner cable within an outer stationary sheath to accomplish helicalscanning (e.g., FIG. 15).

Exemplary ILSI Catheter:

It can be possible to provide a miniaturized leached fiber bundles(e.g., diameter approximately 250 μm, length=1 m). Utilizing a fibersize of approximately 8 μm, with a partial core area of approximately0.4, approximately 2000 collection fibers can be incorporated to obtaina fiber bundle with sufficiently low cross-talk to transmit specklepatterns. A central light delivery fiber can be included forillumination. Micro-optical components including a focusing lens, custompolarizer and rod mirror can be optimized, tested and affixed to thedistal bundle face. A variety of different lenses can be investigated,including GRIN lenses and custom-fabricated ball lenses, and optimizedto provide a focused illumination spot size of approximately 20 μm andimaging FOV of approximately 500 μm. Miniaturization and fabrication ofoptical components can be conducted to achieve a target optical coresize of approximately 300 μm. The optical core can be affixed within adriveshaft cable (e.g., Asahi Intec, CA) to convey torque from a motorto enable helical scanning. A transparent rapid-exchange sheath with aguide wire port can house the catheter cable assembly, and can be testedfor optical clarity.

(ii) Exemplary motor drive assembly can include an optical rotaryjunction (“ORJ”) that can couple light with the rotating optical core(e.g., FIG. 15). Excellent rotational uniformity (e.g., <10% modulation)and low transmission loss (e.g., <1 dB) in can be provided with ORJsprovided in the exemplary OCT/OFDI systems. (See, e.g., References 60,61 and 85). For example, the ORJ was designed to couple with a singleoptical fiber within the OCT/OFDI catheter while continuously spinningat speeds of approximately 6000 rpm. The ORJ can be provided for the usewith the exemplary ILSI device such that: (a) it can facilitate couplingof light with a rotating optical fiber bundle consisting of multipleoptical fibers, and (b) the exemplary ILSI catheter would not spincontinuously. Instead in order to permit acquisition of the speckleimage time series over about 25 ms at each circumferential location(e.g., based on studies shown in FIG. 13), a stepper motor can beincorporated to rotate the optical core at discrete steps with aresidence time of about 25 ms per step. The exemplary ORJ can include acollimating lens (e.g., L2) affixed at the proximal end of the opticalcore and a motor coupled with the driveshaft to enable rotation. A CMOSsensor (e.g., Mikrotron 1310) can be housed directly within the ORJ, andtransmitted speckle patterns can be imaged via a stationary lens (e.g.,L1). The rotational rate of the catheter can be 1 Hz. A linear pullbackstage can facilitate a translation/pullback during imaging over speedsof about 0.25-1.0 mm/s. Rotational distortion (e.g., <10%) can bemeasured by comparing τ values of aortic plaques with a stationarycatheter (e.g., Table.1)

TABLE 1 Quantitative benchmarks for ILSI device in Aim 1 PerformanceTarget Expected Value Catheter size 2.6-3.0 F (0.8-1.0 mm) Catheterrotation rate ~1 Hz Rotational distortion <10% Lateral (circumferential)~250 μm scan spacing Longitudinal scan pitch 0.25-1.0 (depends onpull-back speed) Dwell time per rotational 25 ms increment Field of View(FOV) ~500 μm Axial resolution mean~100 μm (FIG. 18) Lateral resolutionmena~150 μm (FIG. 18) Penetration depth ~350 μm (FIG. 19) Imaging framerate ~2 kHz (512 × 512 pixels)

(iii) The portable console can be modified to facilitate helical imagingand data visualization. Engineering tasks can include: a) interface tocontrol the motor drive assembly and automated flush devices, and b)software interface design. Similar to the exemplary preliminary studies,a He Ne light source (e.g., 632 nm, 30 mW) can be used for illumination.

Time-varying laser speckle images can be collected at an approximately 2kHz frame rate (e.g., 512×512 pixels).

Reconstruction of Arterial Viscoelasticity Maps:

To obtain sufficient spatial sampling during catheter rotation, alateral spacing of about <250 μm can be utilized between rotationalsteps. Considering the typical coronary circumference of about 10 mm,and the catheter FOV of about 500 μm, 40 discrete steps can facilitateadequate spatial overlap for sufficient circumferential sampling atabout a 1 Hz rotational rate. The longitudinal scan pitch and totalimaging time can be determined by the pull-back speed (e.g., Table 1).

Exemplary 2D Reconstruction:

To evaluate 2D arterial viscoelasticity maps, at each site, τ can becomputed over each speckle image by exponential fitting of the g2(t)curve using previously reported techniques. (See e.g., References 42 and46). The resulting 2D array of discrete τ values can be processed usingspatial filtering and bilinear image interpolation approaches toreconstruct maps corresponding to arterial viscoelasticitydistributions.⁸⁶ NC plaques of high clinical relevance identified by lowτ values (e.g., approximately 5-10 ms) can be selected to exploredepth-resolved analysis.

Exemplary Depth Analysis:

The capability of ILSI to provide 3D depth-resolved distribution of τvalues in NC plaques in vivo is described below. For example, at eachlocation (x,y) over the FOV, windowed cross-correlation can be performedover the speckle time series to obtain g2(t). To ensure sufficientensemble averaging, g2(t) can be measured by averaging severalcross-correlation functions that evolve in time over about a 25 msimaging duration and over neighboring pixels, which can influence themeasured spatial resolution for mapping. The resulting 2D distributionof τ (x,y) can be obtained (e.g., FIG. 16) by exponential fitting ofg2(t) curves. Due to light transport properties, τ (x,y) farther fromthe beam location can be influenced by longer optical paths. Using aMonte-Carlo Ray Tracing (“MCRT”) algorithm, a look up table of the 3Ddistribution of mean penetration depths (z) over the FOV remittanceplane can be created (e.g., FIG. 17), and the corresponding depths foreach τ (x,y) can be determined to provide the depth-resolveddistribution of τ. The process can be repeated at each circumferentialbeam location to reconstruct the full 3D viscoelasticity distribution ofNC plaques.

Estimated Resolution:

Axial resolution can be estimated by the full width-half maximum(“FWHM”) of the penetration depth distribution and the lateralresolution can be determined from the FWHM of the radial scattering PDF.Estimated values using MCRT can be plotted (e.g., FIG. 18). Spatialresolution can degrade with depth (e.g., Table 1). However, oversuperficial depths, the estimated spatial resolution about <100 μm canbe sufficient to evaluate thin caps that can be most clinicallyrelevant. At deeper depths (about >100 μm), resolution approximatelyabout 100-200 μm can be sufficient to evaluate large necrotic cores ofhighest significance. Exemplary methods described herein can be testedon human arteries and phantoms of spatial and depth-varying properties.Axial resolution can be measured by scanning a sample of known G withinscattering media using a motorized stage. Lateral resolution can beverified using a patterned PDMS resolution target.⁸⁷⁻⁸⁹ Utilizingexemplary beam scanning in conjunction with depth-resolved LSI canprovide an important understanding of the viscoelastic properties of thefibrous cap and NC layers to estimate the load bearing capabilities ofclinically significant NC plaques.

ILSI Testing and Validation in Swine:

The human to swine coronary xenograft model (e.g., preliminary studies)can be used to validate the ILSI device for coronary screening. Humancoronary grafts (e.g., 2 per heart x 10 hearts) can be grafted inanaesthetized swine (e.g., N=10) for ILSI validation. The distal startand end of scan locations can be marked by India ink corresponding withthe visible ILSI beam for co-registration with Histology. Scanning canbe performed over an approximately 5 cm pull-back in conjunction with aVisipaque flush. Following ILSI, the grafts can be evaluated usingintracoronary OFDI in vivo. Histology sections can be obtained at 2 mmincrements and co-registered with the corresponding ILSI cross-section.For example, a total of 500 ILSI-OFDI-Histology correlatedcross-sections can be analyzed (e.g., 25 sections/artery×2 arteries×10hearts). Plaque type can be diagnosed at approximately 250 μm spacingusing both Histology and OFDI as, for example, TCFA, THFA, PIT, Fibrousor fibrocalcific, and compared with τ at each site. In NC plaques,fibrous cap thickness can be measured by depth-resolved ILSI and can becompared with Histology. Success can be determined by ANOVA tests toevaluate T difference between groups, based on OFDI and Histologydiagnosis, p<0.05 can be considered statistically significant.

Exemplary Alternate Embodiments

Exemplary Optical Rotary Junction:

In the unlikely event that about >10% deviation in τ can be observedduring catheter rotation, an alternative approach (e.g., recentlydemonstrated in OCT) (see e.g., Reference 90) can be implemented inwhich the optical core can be maintained stationary, and torque can beconveyed to the distal mirror via a driveshaft. It can also be possibleto the use of cone mirrors to conduct LSI. Assuming that cone mirrorscan be sufficiently miniaturized, they can likely provide a viableoption to enable omnidirectional viewing in the ILSI catheter.

Exemplary Alternate Exemplary Catheter Designs:

Exemplary ILSI procedures can be conducted in the conjunction withsaline flushing. In the unlikely event that saline flushing does notsufficiently displace blood, a multi-prong contact based design can beemployed that can maintain endoluminal surface contact during imaging.Similar contact based catheters can be utilized in thermography studiesand can be approved for use in patients. (See, e.g. Reference 24).

Exemplary Depth-Analysis:

The in vivo feasibility of 3D analysis can be performed, and theperformance metrics can be based on 2D maps of bulk τ measurements,based on the results of previous exemplary studies that establish thesignificance of bulk τ for assessing high-risk plaques.

Exemplary Methods:

Optimal Flushing Parameters to Conduct ILSI in Patients:

ILSI can be conducted in vivo while flushing with Visipaque to displaceblood. To calculate the total imaging duration over which clear viewingof the arterial wall can be achieved, further studies have beenconducted in living swine. Flushing with Visipaque was performed at flowrates of about 2-4 cc/s, commonly used in patients, and OFDI wassimultaneously conducted to evaluate blood scattering within the lumen.For a single 10 cc flush at about 3 cc/s, optimal blood clearance andunobstructed viewing of the arterial wall was achieved overapproximately 6 s (e.g., FIG. 19). From these results, it was inferredthat to conduct ILSI in patients, 8 intermittent flushes (e.g., 10cc/flush) of Visipaque can facilitate sufficient blood displacement toscan an approximately 5 cm long coronary segment in less than a minute(e.g., at a scan pitch=1 mm). Thus a low total volume of approximately80 cc of Visipaque can be administered. The average volume safelyadministered in patients can be reported to be about 265±130 ml. (See,e.g., References 92 and 93).

Human ILSI Study:

Following regulatory approval, it can be possible to evaluate coronaryplaque viscoelasticity using ILSI in a cohort of 20 patients with nativeCAD who present at the MGH cardiac catheterization laboratory forpercutaneous coronary intervention (“PCI”). In order to test thefeasibility of the ILSI approach in patients, intracoronary OFDI can beused to provide a microstructural context for ILSI results. Briefly, theculprit lesion can be determined from the patient's angiogram. The OFDIcatheter can be advanced over a guide wire just distal to the culpritlesion. The maximum coronary length scanned can be about 5.0 cm (e.g.,range: 2.0-5.0 cm, imaging/flush parameters calculated below are basedon maximum length). During a 3 s, 3 cc/s flush, the OFDI catheter can bewithdrawn at a pullback speed of about 20 mm/s to scan a 5 cm segment.Following the OFDI procedure, ILSI can be conducted. The ILSI cathetercan be similarly advanced distal to the culprit lesion underfluoroscopic guidance. Safety can be evaluated by monitoring hemodynamicparameters, EKG and development of symptoms during the exemplary ILSIprocedure. The ILSI catheter's rotational rate can be about 1.0 Hz andimaging can be conducted in conjunction with 8 intermittent flushes(e.g., 10 cc) at about 3 cc/s as detailed above to image a matching 5.0cm length in <50 s. The total amount of Visipaque administered for theentire imaging procedure can be <100 cc. It can be expected that theexemplary procedure can add 15-20 minutes to the routine PCI procedure(e.g., typical duration of 120 minutes).

Data Co-Registration and Analysis:

To determine the feasibility of ILSI in patients, ILSI 2Dviscoelasticity maps can be compared with plaque type andmicrostructural information obtained from OFDI. In order to accomplishaccurate data comparisons, digital coronary angiography can be conductedat the start and end of both OFDI and ILSI procedures to permit dataco-registration. Additional landmarks, including the guiding catheter,stent edges and side-branch vessels can be used to improve registrationaccuracy.11 Co-registration in the circumferential direction can be doneby reading the motor encoder positions on the OFDI and ILSI rotaryjunctions. OFDI images can be interpreted using previously establishedmethods to characterize coronary plaques as: TCFA, THFA, PIT, Fibrous orfibrocalcific. (See e.g., References 12, 62, 94 and 95). ILSI-OFDIcorrelations can be evaluated using ANOVA tests to assess thefeasibility of ILSI in measuring distinct τ values based on plaque type.The feasibility of measuring depth-resolved viscoelasticity can beevaluated in NC plaques by co-registering ILSI 2D cross-sectional mapsof τ distributions with corresponding OFDI cross-sections.

Exemplary Potential Problems and Alternative Strategies:

Blood:

Blood in the FOV can cause rapid blurring of speckle due to moving bloodcells. Real-time speckle analysis can be implemented and scan repeatedif τ<1 ms. An alternative solution to detect blood can be to incorporatesimultaneous coronary viewing via the same catheter with a white lightsource and color camera.

Cardiac Motion:

For example, ILSI can be conducted without EKG gating. In the unlikelyevent that cardiac motion can be problematic, EKG gating can beutilized, and the feasibility of ILSI can be tested by evaluatingdiscrete arterial sites predetermined by OFDI.

Nephrotoxicity:

In patients with renal impairment, Lactated Ringers can be used whichhas provided good ILSI results in exemplary studies. In these patientsimaging can be restricted to a <3.0 cm segment.

Culprit Lesion:

In the event that the culprit site can be inaccessible, OFDI and ILSIcan be performed post-PCI.

OFDI:

OFDI-ILSI comparisons can be verified. Since, no intracoronarytechnology exists to measure plaque viscoelasticity metrics in patients,in vivo ILSI feasibility can be tested using OFDI findings that havebeen well established for plaque evaluation. (See, e.g., References 12,62, 94 and 95).

The developed by Snyder (see, e.g., Reference 120) can be applied todetermine the various parameters of the fiber optic bundle as describedherein. CMT can be an approximate analytical approach to study opticalcrosstalk between neighboring waveguides in terms of the couplingbetween guided modes of neighboring waveguides, to fully investigatecoupling between all modes of adjacent fibers. The influence of multiplefiber bundle parameters on inter-fiber crosstalk and the modulation oftransmitted laser speckles can be quantified. Furthermore, fiber bundleparameters can be defined to considerably reduce the modulation oftransmitted speckle patterns caused by mode coupling between and withinmulti-mode cores.

TABLE 2 Specifications of two commercially available OFB Core to coreCore size spacing OFB Type (μm) (μm) NA Type I 4.5 7.4 0.40 Type II 3.56.5 0.40

Exemplary Devices and Methods for Achieving Omni-Directional Viewing

In an exemplary embodiment (e.g., FIG. 15) described and shown herein,the motor drive assembly can be used to conduct helical scanning of thevessel. The motor drive assembly can be modified to achieve a 360-degreerotation of the catheter, or it can be rotated over a limited, orpartial angle, to illuminate and image a section or sector of the lumencircumference at one time. The exemplary design can include an opticalrotary junction (“ORJ”) that can couple light with the rotating opticalcore. In OCT catheters, the ORJ can be designed to couple light with asingle optical fiber while continuously spinning at speeds ofapproximately 6000 rpm. The ORJ provided for the exemplary ILSI devicecan have two exemplary features: (i) it can facilitate coupling of lightwith a rotating catheter, and can include a fiber bundle with multipleoptical fibers, and (ii) the ILSI catheter can be prevented fromspinning continuously. In order to permit measurement of speckledecorrelation over about 25 ms at each circumferential location, a motordrive can be incorporated to rotate the optical core at discrete stepswith a residence time of about 25 ms per step. The ORJ can include acollimating lens at the proximal end of the optical core to couple lightinto a central illumination fiber, and a motor coupled with thedriveshaft to enable rotation. An exemplary CMOS sensor can be houseddirectly within or connected to the ORJ, and can transmit specklepatterns imaged via a stationary lens. The exemplary rotational rate ofthe catheter can be about 1 Hz. A linear pullback stage can facilitatetranslation/pullback during imaging over speeds between, but not limitedto, about 0.25-1.0 mm/s. In this exemplary design, the inner opticalcore can be affixed within a driveshaft cable to convey torque from amotor, to facilitate helical scanning. Some or all of the inner cable(e.g., the optical fiber bundle and distal optics) can rotate.

In another exemplary embodiment of the present disclosure, the inneroptical core can remain stationary, and mechanical torque can beconveyed only to the distal mirror that can be affixed to the driveshaftcable. In still another exemplary embodiment of the present disclosure,a ring of illumination fibers surrounding the collection bundle can beused to illuminate the tissue, and the distal mirror can be rotated. Viaa ring of illumination fibers, the tissue can be illuminated using lightwith a single wavelength, or with multiple fibers illuminating thetissue using different wavelengths of light. This can facilitate abetter separation and a more robust analysis of speckle patterns. Therecan also be no are no moving parts. Instead a multi-faceted mirror(e.g., figures described below) can be incorporated at the distal endfor omnidirectional viewing of the entire circumference of the lumen(e.g., 360 degree omnidirectional viewing). The multi-faceted mirror canbe a cone mirror. Alternatively, or in addition, acone-polygon/pyramidal shaped mirror can be used in which one or more ofthe reflecting surfaces can include one or more flattened reflectivefacets. Multiple illumination fibers can illuminate different facets ofsurfaces of the multi-faceted mirror, and speckle images can becollected simultaneously from 2 or more facets. During image processing,images obtained from multiple facets can be unwrapped and reconstructedto visualize the entire circumference of the luminal tissue of interestas shown below.

In another exemplary embodiment of the present disclosure, the opticalcore can remain stationary, and a rotating galvo-mirror can beincorporated at the distal end. The mirror can be provided to fit withina less than about a 1 mm catheter sheath.

In some or all of the exemplary embodiments, an optional circularpolarizer can be included to reduce the influence of back-reflections orspecular reflections emanating from surfaces of the catheter sheath, orfrom the surface of the tissue of interest. Specular reflections can beremoved using software during post-processing of speckle images. Thiscan be achieved by, for example, thresholding the image based on thetemporal statistics of speckle fluctuations where pixels with negligiblespeckle fluctuation can be masked out during analysis. This can ensurethat only light, or other electromagnetic radiation, that has undergonemultiple scattering can be analyzed to measure an index of tissueviscoelasticity.

Preventing a receipt of the same polarization from returning in theradiation (e.g., light) can be beneficial in reducing back-reflectedlight of the similar polarization state that has scattered only once, ora few times, from the catheter surfaces and/or surface of tissue, whichcan otherwise increase the strong background intensity and confound thesensitivity of the device in measuring laser speckle intensityfluctuations scattered from tissue. The polarizer can be replaced bycomputer software, or other methods, which can include spatial andtemporal filtering that can similarly prevent back-reflections of lightof the same polarization state. Filtering (e.g., to replace thepolarizer) can be achieved by removing pixels in the image in which theintensity fluctuation can be zero, or negligible, over time caused byreflected light that has maintained its polarization state following asingle or few scattering events. Thus, fluctuating speckles causes bydepolarized light, which has undergone multiple scattering throughtissue, can be analyzed to measure the mechanical properties of tissue.

Exemplary Image Processing and Visualization

Exemplary image processing procedures according to an exemplaryembodiment of the present disclosure can include image unwrapping (e.g.,FIGS. 33B and 33C) removal of pixilation artifact (e.g., FIG. 33F),spatio-temporal analysis of speckle fluctuations and visualization usinga time constant color map and display. Various procedures can be useddepending on the complexity of measurement that is required.

An exemplary procedure can include measuring measure the speckledecorrelation curve, g2(t), by cross-correlation of multiple speckleframes obtained over the time series, conducting spatial and temporalaveraging over multiple g2(t) curves and determining the time constantby exponential fitting over short time scales. The speckle time constantcan be reported as an index of tissue viscoelasticity. To extract 3Ddepth information, it can be possible to use a hybrid approach thatcombines Monte-Carlo ray tracing (“MCRT”) with spatio-temporal windowedanalysis of speckle patterns. This exemplary procedure has beenpreviously been validated in necrotic core coronary plaque. (See e.g.,Reference 43). It can also be possible to modify this exemplaryprocedure to account for changes in the number of scattering events as afunction of depth.

Additional exemplary procedures can be provided to measure the elasticand viscous moduli of plaques directly from laser speckle patterns.g2(t) can be related to mean square displacement (“MSD”) of lightscattering particles within the plaque, and the MSD can be related toelastic and viscous moduli via the Stokes Einstein's formalisms. It canalso be possible to display 2D maps of time constant by using spatialaveraging, spatial filtering along with bilinear image interpolationtechniques. It can be possible to further apply the above apparatus andmethods for use in an exemplary helical/cylindrical display and for useco-registration for intra-coronary mapping. (See e.g., FIG. 1).

Exemplary Efficacy of LSI

In order to validate the use of the exemplary LSI to measure tissuemechanical properties, LSI results of time constant (e.g., on testphantoms and tissue) can be compared with mechanical testing using arheometer, which has been previously shown to exhibit excellentcorrelation in these studies (e.g., R=0.79, p<0.05). (See e.g.,Reference 42).

In order to validate capability of LSI to discriminate between plaquemechanical properties, LSI time constants compared withHistopathological diagnosis of tissue type can be performed by aPathologist. Differences between time constant measurements fordifferent tissue types can be evaluated using ANOVA tests. Both ex vivoand in vivo studies show distinction can be good between NC plaques andother plaque types (e.g., including normal, fibrous, calcific andpathological intimal thickening). (See e.g., References 46, 70 and 97).Since plaque mechanical properties can be dependent on collagen andlipid, correlation between time constant and collagen and lipid contentwithin the measurement area of interest can be performed. Collagencontent can be measured using Picrosirius staining, polarized lightmicroscopy measurements and lipid using oil-red O, as well asimmunohistochemical staining to detect Apolipoprotein B complex on LDLcholesterol. (See e.g., References 42, 45 and 95).

Sensitivity and Specificity of the exemplary LSI has been measuredpreviously in ex vivo validation studies. (See e.g., Reference 42). Thiscan be done by receiver operating characteristic (“ROC”) analysis. Theexemplary test can evaluate the capability of LSI to distinguishmechanical properties of thin cap fibroatheroma (“TCFA”) plaques asthese can be considered more unstable plaques of clinical significance.The presence of TCFA can be considered +ve diagnosis, and all othertissue types can be considered −vediagnosis. Both sensitivity (e.g.,100%) and spec (e.g., 92%) can be maximized, which can be used with adiagnostic threshold of time constant of about 76 ms. These exemplarystudies can be similarly performed for in vivo studies.

Sensitivity=True Positive/(True positive+False Negative) andspecificity=True Negative/(False Positive+True Negative). Flushing usingcontrast agents, lactated ringers or dextran solution can be routinelyused in the catheterization laboratory for OCT and angioscopy imaging.Additionally, a contrast agent can be routinely used for angiography fora number of years. No major technical challenges can be expected in theflushing process, and this mechanism can be manual or automated. It canbe possible to provide procedures to optimize flushing for ILSI (e.g.,parameters: type of flushing agent, rate of flush, volume of flush,etc.) similar to OCT/angioscopy.

A practical challenge can potentially be inadequate flushing. Usually,the presence of blood can be easily detected as it can cause very rapidspeckle decorrelation, and can provide a distinct time constantsignature. To detect problems with inadequate flushing, it can bepossible to include white light source to conduct color angioscopy intandem through the same catheter. Alternately, various other exemplarymethods can be used (e.g., a dual wavelength illumination to measureabsorption due to presence of blood).

If flushing still poses a challenge, proximal balloon occlusion can beused for a short period of time. Flushing for clearing blood from thefield of view during optical imaging can be routinely employed inangioscopy as well as and OCT/OFDI. Over 1000 studies have beenpublished, and this exemplary method is well accepted by clinicians.Furthermore, flushing the coronary tree with contrast agent has beenroutinely used for many decades in conventional angiography procedures.

ILSI can be conducted, in vivo, while flushing with contrast agent orlactated ringers can be used to displace blood. The exemplary flushingmechanism is described in FIG. 36. Using calculations based on exemplaryOCT studies in swine (e.g., FIG. 37) to conduct ILSI in patients, theuse 8-10 intermittent flushes (e.g., 10 cc/flush) of diluted contrastagent or lactated ringers Visipaque can permit sufficient blooddisplacement to scan an approximately 5 cm long coronary segment in lessthan a minute (e.g., at a scan pitch=1 mm). Thus, it can be expectedthat a low total volume about 80-100 cc of flushing agent can beadministered during ILSI, which can be below the average volume that issafely administered in patients. (See e.g., References 92 and 93).

According to a further exemplary embodiment of the present disclosure,it is possible to provide a miniaturized (e.g., <1 mm) ILSI catheterthat can be safely guided through the coronary artery to conductintracoronary mapping. It can be beneficial to keep the exemplary deviceas similar to a commercially available (e.g., regulatory approved) IVUScatheter and system as possible. It can also be possible to confirm ILSIcatheter characteristics (e.g., damage to endothelium, trackability,pushability and ease of use) are similar to an exemplary IVUS catheter.

Exemplary Analysis of Omni-Directional Mirror Configurations:

Exemplary embodiments of exemplary omni-directional catheters caninclude reflective arrangements or at least partially-reflectivearrangement that can include multiple facets at the distal tip of thecatheter to direct electromagnetic radiation to the cylindrical lumen,and to collect reflected speckle patterns from multiple sites of thelumen circumference without rotating the catheter.

FIGS. 38A-38C illustrate an exemplary cone-polygon/pyramidal mirror foromni-directional (e.g., laser speckle, etc.) imaging. The image is atthe bottom of the image plane for the object that is at the top of themirror. At the image plane, the central part can have more aberrationsand a larger spot radius, while the edge can have less aberrations andsmaller spot radius. The spot size at the edge can be smaller than afiber's cross-section surface. Additionally, the off-axis object cancause overlap of the images if the off-axis object has an enough largedistance.

FIGS. 38E-38H illustrate an exemplary cone mirror-side view for verticalfocal plane. The image is at bottom of the image plane for the object atthe top of the mirror. At the image plane, the central part can havemore aberrations more aberration and a larger spot radius, while theedge can have less aberrations and smaller spot radius. The spot size atthe edge can be smaller than a fiber's cross-section surface. Theoff-axis object can cause overlap of the images if the off-axis objecthas an enough large distance. The horizontal aberration can be verystrong due to curvature of the cone mirror.

FIGS. 38I-38L illustrate an exemplary cone mirror top view forhorizontal focal plane. The vertical focal plane and horizontal focalplane can be at different location, (approximately 1 mm difference.Strong horizontal image aberrations can be seen, and can cause severeimage overlap horizontally. Also present, is a big spot size, and aninadequate horizontal resolution.

FIGS. 39A-39H illustrate exemplary images obtained using variousexemplary omni-directional mirror configurations. Exemplary selectionsof fiber bundle parameters can be used to reduce inter-fiber cross-talkduring laser speckle imaging.

Optical fiber bundles can typically incorporate thousands hexagonallyarranged individual optical fiber cores as shown in FIG. 20A. Theanalysis of mode coupling between all of the fiber cores can be far toocomplicated and numerically intensive to be calculated. However asimplified system of 7 parallel fibers can be used to model the couplingbetween the modes of these fibers (see, e.g., References 115-117) andthe result can be easily extended to an entire fiber bundle. Here, amulti-core optical fiber system of 7 hexagonally arranged cores embeddedin a uniform cladding material as shown in FIG. 20B, can be used. Thefiber bundle specifications can be based on two commercially availableleached fiber bundles (e.g., SCHOTT North America) and are listed inTable 2 above. These two types of fiber bundles were chosen becausetheir specifications can be typical for the fiber bundles used in LSI.(See, e.g., Reference 100).

Coupled mode theory (see, e.g., References 114 and 120-122) can be acommon theoretical model used to obtain approximate solutions to thecoupling between waveguides of multiple waveguides systems. Compared tothe normal mode expansion method (see, e.g., Reference 115), in whichthe field can be expanded in terms of normal modes solved from Maxwell'sequations with the boundary conditions of the entire complicatedstructure, in CMT the field can be decomposed into the modes of eachindividual waveguides (see, e.g., Reference 114):

$\begin{matrix}{{{E\left( {x,y,z} \right)} = {\sum\limits_{v}{{\alpha_{v}(z)}{e_{v}\left( {x,y} \right)}{\exp\left( {i\;\beta_{v}z} \right)}}}}{H\left( {x,y,z} \right)} = {\sum\limits_{v}{{\alpha_{v}(z)}{h_{v}\left( {x,y} \right)}{\exp\left( {i\;\beta_{v}z} \right)}}}} & (3)\end{matrix}$

where av can be a complex amplitude of vth mode; ev and hv can beelectric and magnetic components of normalized mode field of eachindividual fiber, respectively; βμ can be the mode propagation constantof mode μ; z can be the propagation distance along the fiber bundle andthe summation over v runs through all modes of all individual fibers.The effective refractive index of mode Er can be defined as neff=βμ/k,where k=2π/λ, can be the wave number. For complex structure, thecomplete set of the normal modes can be difficult to solve out (see,e.g., Reference 115) while in CMT, modes of each core of fiber bundlecan be solved independently. The complex amplitude of modes can beobtained by solving the coupled mode equation (see, e.g., Reference 114)which can describe how the amplitude can vary with propagation distancez along with the length of the coupled waveguides, where, for example:

$\begin{matrix}{{\frac{{da}_{v}}{dz} = {\sum\limits_{\mu}{i\;\kappa_{v\;\mu}a_{\mu}\mspace{14mu}{\exp\left( {i\;{\Delta\beta}_{v\;\mu}z} \right)}}}},} & (4)\end{matrix}$

where

$\kappa_{v\;\mu} = {c_{vv}\left\lbrack {c^{- 1}\overset{\sim}{\kappa}} \right\rbrack}_{v\;\mu}$

can be the mode coupling coefficient between mode v and The couplingcoefficient can be directly related to the degree of overlapping of modefield. The coupling coefficient kvμ along with the difference in modepropagation constant Δβ_(vμ)=β_(μ)−β_(v) decide the coupling strength ofμth, mode to vth mode. The mode coupling coefficient c_(vμ) can bedetermined by the overlap coefficient of mode fields (ev, hv) and (eμ,hμ) and the perturbation {tilde over (κ)}_(vμ) of mode μ to the mode v.Here the element of matrix c_(vμ)=∫∫(e*_(v)×h_(μ)+e_(μ)×h_(v)*)□zdxdyand c_(vμ) for the normalized mode field by definition. The element ofmatrix x can be given by, ω∫∫Δε_(μ)e_(v)*

_(μ)dxdy, where ω can be the angular frequency of the laser light andΔε_(μ)(x, y)=ε(x, y)−ε_(μ)(x, y) can be the difference between thedielectric constant of the whole multi-core structure and the dielectricconstant of the structure with only the individual fiber supporting themode μ.

To evaluate the modulation of laser speckle patterns during transmissionthrough the optical bundles, laser speckle fields can first benumerically generated (see, e.g., Reference 97) by Fourier transform thefield with random phase. The polarization of speckles can be chosenalong with the linear polarization of fundamental modes of fibers. Thegenerated speckle fields can then be decomposed into HE, EH, TE and TMfiber modes of individual fibers. The complex amplitude of each guidedfiber mode at z=0, av(0), can be given by for example:

α_(v)(0)=∫∫e _(v) *□E ₀dxdy,  (5)

where E₀ can be the generated speckle electric field. By solving the Eq.(4) for each propagating mode with the initial value of a_(v)(0), thecomplex amplitude at propagation distance z can be obtained. Thetransmitted speckle patterns can then be reconstructed by linearlycombining the fields of all fiber modes with its amplitude. Themodulation of the transmitted speckles can then be evaluated by thecorrelation coefficient of the intensity patterns between reconstructedspeckle patterns at different positions along the length of bundles andthe reconstructed speckle patterns at z=O (see, e.g., Reference 27),where, for example:

$\begin{matrix}{{{C(z)} = \frac{\overset{\_}{\left( {{I\left( {x,y,z} \right)} - {{\overset{\_}{I}(z)}\left( {{I\left( {x,y,{z = 0}} \right)} - {\overset{\_}{I}\left( {z = 0} \right)}} \right)}} \right.}}{{\sigma_{1}(z)}{\sigma_{1}\left( {z = 0} \right)}}},} & (6)\end{matrix}$

where I(x,y,z) can be the intensity of speckle electric field E(x, y,z)=Σ_(v)α_(v)(z)e_(v)(x, y)exp(iβ_(v)); Ī(z) and σ₁(z) can be thespatial average and standard deviation of the intensity patterns atdifferent z, respectively. Here x, y can be the transverse coordinatesof the points within the 7 core areas. C=1 can indicate that two specklepatterns can have same spatial fluctuations and so totally correlatedwhen C=0, the speckles patterns can have no correlation. Thus theaverage of C over 20 speckle realizations can be used to measure thespeckle modulation.

Exemplary Speckle Image Processing Exemplary Elimination of PixelationArtifact

To conduct ILSI, a small-diameter, flexible optical fiber bundle can beused to transmit the laser speckle patterns reflected from the coronarywall to the high speed CMOS camera at the proximal end of the imagingcatheter. However, the hexagonally assembled optical fibers can create ahoneycomb-like pixelation artifact, as shown in FIG. 26A. Each whiteround area 2605 is a fiber core. The dark gaps 2610 between cores arethe fiber cladding. Due to these gaps, the speckle images may not becontinuous. These gaps can also reduce the number of pixels covered byeach speckle, and can therefore reduce the efficiency of spatial averagein calculating the temporal statistics of speckles patterns, such as thespeckle autocorrelation, within a certain spatial area. Thus, the areacan be enlarged to include more pixels to obtain an adequate spatialaverage. Consequently the spatial resolution of the exemplary maps ofthe arterial viscoelasticity distribution constructed from the specklefluctuations can be degraded. This degradation can limit the ability todistinguish morphological features of tissues, such as the size andshape of plaques. To eliminate the pixelation artifact, two exemplarynumerical methods can be applied for two distinct speckle size regimes(e.g., speckle sizes larger than core spacings and speckle sizes smallerthan core spacings).

Exemplary Speckle Size Larger than Core to Core Spacing

According to the Nyquist-Shannon sampling theorem, if the speckle sizecan be larger than the core spacing between two neighboring cores, thespatial frequencies of the speckle patterns can be lower than that ofthe hexagonal pattern of fibers. Therefore, the hexagonal pattern offiber cores in Fourier domain can be removed by applying a low passfilter whose cut-off frequency can be no less than the highest spatialfrequency of the speckle pattern.

The recorded raw images can be transformed (e.g., using a Fouriertransform) to spatial frequency domain and then multiplied by a low passfilter HB(u,v) (e.g., a Butterworth low pass filter), which can provide,for example:

$\begin{matrix}{{{H_{B}\left( {u,v} \right)} = \frac{1}{1 + \left( {{D\left( {u,v} \right)}\text{/}D_{0}} \right)^{2n}}},{{D\left( {u,v} \right)} = \left\lbrack {\left( {u - u_{0}} \right)^{2} + \left( {v - v_{0}} \right)^{2}} \right\rbrack^{1\text{/}2}},} & (7)\end{matrix}$

where u and v can be the coordinates in the Fourier domain, u₀ and v₀can be the center of the filter, D₀ can be the cut-off frequency and ncan be a positive integer. A Butterworth filter can be used because itis a low pass filter with minimal ringing artifacts induced by the shapeof the cutting edge owing to the Gibbs phenomenon. Then the product ofthe Fourier transform of the speckle pattern and the Butterworth filtercan be Fourier transformed back to spatial domain to reconstruct thespeckle patterns.

FIG. 26B illustrates a raw speckle images obtained by an exemplary ILSIcatheter from a coronary phantom. Areas 2615 and 2620 are the specklepatterns reflected from the two opposite area in the phantom. Thehoneycomb-like pixelation artifact can be easily seen in the FIG. 26B.FIG. 26C shows the Fourier transform of the raw image. The hexagonalpattern 2625 of the local maximums in FIG. 26C can be due to thehexagonal assembled optical fiber cores. In

FIG. 26D the Fourier transform is superposed by a Butterworth filter.The filter cutoff frequency can be equal to the spatial frequency of thefiber cores. Area 2630 gray area is the rejected high frequency area bythe low pass filter. The 6 first order hexagonal arranged dots 2635 areat the cutoff region of the low pass filter. If the filter cutofffrequency is even smaller, the entire periodic pattern can be filteredout such that the pixelation artifact can be removed.

Exemplary Speckle Size Smaller than Core to Core Spacing

For the speckle patterns with speckle size smaller than core spacing,the spatial frequencies of the speckle pattern can be higher than thatof the hexagonal pattern of fibers. Thus, simply applying the low passfilter can also remove the high frequency components of the originalspeckle patterns. The reconstructed speckle image can also be heavilyblurred due to loss of high frequency information. A notch band-rejectedfilter can be applied for selectively eliminating hexagonal pattern inthe Fourier domain. (See e.g., Reference 126). A notch reject filter canbe formed as the product of multiple Butterworth band-reject filterswhose centers are the centers of hexagonal bright spots in the Fourierdomain. The notch filter HNF can be designed as, for example:

$\begin{matrix}{{{H_{NF}\left( {u,v} \right)} = {\prod\limits_{k = 1}^{N}\;{H_{k}\left( {u,v} \right)}}}{{{H_{k}\left( {u,v} \right)} = {1 - \frac{1}{1 + \left( {{D_{k}\left( {u,v} \right)}\text{/}D_{0}} \right)^{2n}}}},{{D_{k}\left( {u,v} \right)} = \left\lbrack {\left( {u - u_{k}} \right)^{2} + \left( {v - v_{k}} \right)^{2}} \right\rbrack^{1\text{/}2}},}} & (8)\end{matrix}$

where u_(k) and v_(k) can be the center of the kth bright spot in theFourier domain and Π can be the multiplication symbol. An example of thenotch filter is shown in FIGS. 27A and 27B. As shown in FIG. 27A,hexagonal arranged maximums of the Fourier transform of the raw speckleimage can be covered by dots 2705. The periodic dots 2705 in FIG. 27Aare the rejected areas of the notch filter. A 3D view of the exemplarynotch filter is shown in FIG. 27B. After the notch filter can beapplied, the pixelation artifact can be removed. However, thereconstructed speckle patterns can contain the components whose spatialfrequencies can be higher than the spatial frequencies of the originalspeckle patterns. To remove the unnecessary high frequency components,an additional Butterworth low pass filter can be applied to the specklepatterns retrieved by using the notch filters. The cutoff frequency ofthe low pass filter can be set to be larger than the spatial frequenciesof the original speckle patterns. The reconstructed speckle pattern isshown in the FIG. 30A. Area 3005 of FIG. 30A can be the area where thepixel intensity can be zero. Outlined regions 3010 and 3015 are thespeckle patterns that can have enough intensity to calculate theirtemporal statistics.

Exemplary Quantifying Spatial-Temporal Fluctuations of Speckle ExemplaryTemporal and Spatial Normalization of Speckle Patterns.

In addition to the Brownian motion of light scattering particles,various other effects, such as the fluctuations of output power of lasersource, can also cause the fluctuations of speckle intensity. In orderto precisely measure the rate of speckle intensity, temporalfluctuations due to the motion of light scattering, the intensity ofeach pixel can be divided by the spatially averaged intensity of thecorresponding frame. The averaged intensity for each frame can becalculated by averaging the intensity over all pixels. The averagedintensity can also be temporally smoothed to remove the random noise.FIG. 28A shows the variation of the total intensity of the speckles withtime. Line 2805 represents the smoothed total intensity. FIG. 28B showsthe same total intensity over the imaging time after the pixel intensityis divided by the smoothed average intensity.

To construct the 2D maps of the viscoelasticity of vessel walls, thespatial variation of speckle intensity due to the spatial profile of theillumination light can also affect the precision of the measurement ofthe speckle fluctuation rate. This can be because the statistics ofspeckle fluctuations can be dominated by the pixels with high intensity.Thus, the pixel with strong intensity can have more weight than thepixel with low intensity in calculating the statistics of specklefluctuations. To remove this effect, the averaged speckle patterns overall frames can be calculated. Then the averaged speckle pattern can bespatially smoothed to remove the residual granular patterns of speckles.A spatially smoothed speckle pattern average over frame sequence isshown in FIG. 29. The intensity of each pixel can be divided by thecorresponding pixel intensity of the spatially smoothed speckle patternaverage over imaging time. Therefore, all the pixels can equallycontribute to the calculation of the temporal statistics of specklefluctuations.

Exemplary Speckle Intensity Autocorrelation

In order to characterize the rate of speckle temporal fluctuations andfurther map the viscoelastic properties of vessel walls, the temporalautocorrelation of the speckle intensities g₂(Δt) can be calculated as,for example:

$\begin{matrix}{{g_{2}\left( {\Delta\; t} \right)} = \left\langle \frac{\left\langle {{I(t)}{I\left( {t + {\Delta\; t}} \right)}} \right\rangle_{pixel}}{\sqrt{\left\langle {I(t)}^{2} \right\rangle}\sqrt{\left\langle {I\left( {t + {\Delta\; t}} \right)}^{2} \right\rangle_{pixel}}} \right\rangle_{t}} & (9)\end{matrix}$

where I(t) and I(t+Δt) can be the pixel intensities at times t and t+Δt,and < > pixels and < >_(t) can indicate spatial and temporal averagingover all the pixels and over the imaging time respectively. However thedirect light reflection from the outer sheath and/or other stray lightin the ILSI catheter can lead to the constant background which canintroduce erroneous speckle intensity correlation and the high plateaulevel of g2(Δt) curve. To resolve this issue, the autocovariance (seee.g., Reference 127) of the speckle patterns g2(Δt) can be calculated,where, for example:

$\begin{matrix}{{C\left( {\Delta\; t} \right)} = \left\langle \frac{\left\langle {\left( {{I(t)} - \left\langle {I(t)} \right\rangle_{pixel}} \right)\left( {{I\left( {t + {\Delta\; t}} \right)} - \left\langle {I\left( {t + {\Delta\; t}} \right)} \right\rangle_{pixel}} \right)} \right\rangle_{pixel}}{\sqrt{\left\langle \left( {{I(t)} - \left\langle {I(t)} \right\rangle_{pixel}} \right)^{2} \right\rangle}\sqrt{\left\langle \left( {{I\left( {t + {\Delta\; t}} \right)} - \left\langle {I\left( {t + {\Delta\; t}} \right)} \right\rangle_{pixel}} \right)^{2} \right\rangle_{pixel}}} \right\rangle_{t}} & (10)\end{matrix}$

C(Δt) can determine the correlation between the fluctuations aroundaverage of the intensity.

C(Δt) can calculate the correlation between the intensity fluctuationsaround its ensemble average instead of between the intensity itself ing2(Δt). Because the intensity can include both the speckle intensity andthe intensity of the background, if the background light cannot beneglected, the constant background between the intensity can lead toimprecise g2(Δt). Since the fluctuations of the intensity can come fromthe time-varying speckle, the correlation between the intensityfluctuations can more precisely measure the rate of the speckle temporalfluctuations. At the end, the g2(Δt) or C(Δt) can be fitted to anexponential function f(Δt)=a*exp(−tΔ/τ)+c where t can be the time, thefitting parameter τ can be the decay rate of the speckle correlationfunctions, a and c are the other fitting parameters. τ can also betermed as time constant. This exemplary process can be repeated tocalculate spatial and temporal speckle fluctuations from all facets ofthe omni-directional mirror incorporated in the exemplary ILSI catheter.

Exemplary Time Constant Mapping and Visualization

To construct 2D maps of the viscoelasticity of tissues, whole imagingarea can be divided, as shown in FIG. 27A, into multiple small windows(e.g., 40 by 40 pixel windows). The autocorrelation, or theautocovariance of the speckles within each window can be calculatedsimilar to the above. Each window can have an approximately 50% areaoverlapped with its 4 neighbors (e.g., top, bottom, left and rightneighbors). The different C(Δt) curves for different small windows inthe region outlined by area 2720 in FIG. 27A are shown in FIG. 30B. Eachcurves 3020 is a C(Δ(a curves s IG. 27A r Each curve 3025 is theexponential fit to the corresponding blue C(Δ(the ex. Then, the timeconstants for all windows can be retrieved from the exponential fit. Thespatially discrete time constants can then be bi-linearly interpolatedto construct a smooth map of the time constants.

In order to test the exemplary image processing, an Acrylamide gelphantom in a 3D printed mold with 5 slots can be prepared. Each slot canbe filled with different gel with different viscoelasticity. Theexemplary mold and the exemplary gel filled in are shown in FIG. 31A.The gel A contains 4% Acrylamide and 0.025% of bisacrylamide. Gel Bcontains 5% Acrylamide and 0.025% of bisacrylamide. Gel C contains 5%Acrylamide and 0.055% of bisacrylamide. Gel A has low viscosity whilegel C has high viscosity. 3 different time constant maps at 3 differentpositions in each slot are shown in the FIGS. 31B-1 and 31B-2. As shownin FIGS. 31B-1 and 31B-2 a big difference between the maps of the gel Aand C can be observed, as well as between and between the maps of gel Aand B. The differences between the 3 maps be obtained at differentpositions of the same gel are relatively small.

To test the above exemplary methods, a phantom can be prepared using asmall piece of swine aorta. A small amount of fat emulsion can beinjected with low viscosity between layers of the aorta to mimic thelipid pool of the coronary plaques. Then, the piece of aorta can bewrapped into a small tube (e.g., approximately 3-4 mm in diameter). Theswine aorta with injected fat is shown in FIG. 31C. The exemplary ILSIcatheter can be inserted into the tube of aorta and the time varyingspeckle patterns reflected from the areas of the tube illuminated by theillumination fibers of the catheter can be recorded. At eachlongitudinal position along the coronary, four τ maps can beconstructed. Then the catheter can be pullback a short increment to anew position and the imaging can be performed again. Then all the τ mapsat different positions along the coronary can be longitudinal stitchedtogether to form 4 long τ maps. All the τ maps can be stitched togetherand wrapped on the surface of a cylinder to create 2D cylindrical mapsof the viscoelasticity of the coronary.

An example of wrapping a 2D τ map to form a cylindrical view of the mapsis shown in FIG. 32A. It can be wrapped onto the surface of a cylinderto form a cylindrical view of the arterial viscoelasticity map (e.g.,FIG. 32B). At each longitudinal position, the circumferentialdistribution of the τ values can be displayed by cross-sectional ring(e.g., FIG. 32C).

At each position along the coronary, four τ maps can be constructed. Allthe τ maps can be stitched together and wrapped on the surface of acylinder to create 2D cylindrical maps of viscoelasticity of thecoronary. An example of wrapping 2D maps to form a cylindrical view ofthe maps is shown in FIG. 32.

Exemplary Other Measure of the Speckle Fluctuation Rate

Time-varying speckle fields can arise from the interference of laserlight scattered by the moving particles in a complex media such astissue contain locations of zero intensity. Since both the in- andout-of-phase components of the field can vanish at the position wherethe intensity can be null, the phase can be undefined there. Thelocations with zero intensity and undefined phase can be called phasesingularities, also called an optical vortex. In addition to thetemporal intensity fluctuations of the speckle patterns, the Brownianmotion of light scattering particles in tissue can also cause the phaseof the speckle field. Therefore, the locations of the optical vorticescan also change with time. Thus, the speckle fluctuation rate and thedisplacement of the optical vortices between speckle frames can bestrongly correlated. The spatial locations of the phase singularitiescan be tracked over all frames of the speckle sequence. The averagedmean squared displacement of the speckle vortices can serve as anothermeasure of the speckle fluctuation rate, can measure the viscoelasticityof tissues. AS the phase of speckle patterns may not be measured usingthe current ILSI catheter, an exemplary Hilbert transform can be used togenerate the pseudo-field U(x,y) (see e.g., Reference 128), where, forexample

U(x,y)=I(x,y)+iH{I(x,y)}

where I(x,y) can be the speckle intensity pattern and H{I(x,y)} can bethe Hilbert transform of I(x,y). Then the phase of the U(x,y) can becalled the pseudo-phase φ(x,y), which can be, for example:

${\varphi\left( {x,y} \right)} = {\tan^{- 1}{\frac{H\left\{ {I\left( {x,y} \right)} \right\}}{I\left( {x,y} \right)}.}}$

The temporal-spatial behavior of the optical vortices of thepseudo-phase can be similar to the behavior of the optical vortex of thereal phases. (See e.g., Reference 128). The locations of the phasesingularity can be obtained by calculating the phase change in acomplete counterclockwise circuit around the phase singularity. If therecan be a singularity within the closed circuit, the phase change can be±2π rad. This phase singularity can be described in terms of atopological charge of ±1. Phase singularities of opposite signs can becreated or annihilated in pairs with the evolvement of the specklefield.

FIGS. 32D and 32E show exemplary intensity pattern and the pseudo-phaseof this speckle intensity patterns, respectively. The locations of phasesingularities with positive and negative charge are indicated by element3205 red “+” and element 3210 “o” in the FIG. 32F. The underground area3215 is the pseudo-phase of the speckle pattern.

Two speckle pattern sequences with 50 and 100 frames can be selected.Their temporal autocorrelation g2(t) of the intensity patterns are shownin FIG. 32G. From FIG. 32G, it can be seen that the g2(t) curve of thespeckle sequence with 50 frames can decay much faster than the g2(t)curve of the speckle sequence with 100 frames. For both sequences, theirpseudo-phase can be generated, and the locations of the vortices of allframes can be determined. These locations are then plotted in FIG. 32H.The positively charged vortices are plotted as stars 3220, and thenegatively charge vortices are plotted as circles 3225. The locations ofeach individual vortex over several frames can trace a path called avortex trail. One example of a trail of an optical vortex of eachspeckle sequence is outlined in FIGS. 32H and 32I. By comparing FIGS.32H and 32I, the trails of the vortices can be seen, and are quite longand straight in a slowly varying sequence (e.g., FIG. 32I). In therapidly decorrelating speckle sequence (e.g., FIG. 32H), the vorticestrails are shorter and tortuous. The straight and long trail can meanthat the vortices stay at the same position for long time and thedisplacement of the vortex between two consecutive frames can be small.Therefore, the mean squared displacement of the optical vortices can beinversely related to the time constant of the autocorrelation of thespeckle intensity patterns, and can serve as an additional measure ofthe viscoelasticity of the tissue. An advantage of utilizing thetemporal-spatial behavior of the optical vortices can be that it mayonly a need few frames to obtain the adequate statistics of the meansquared displacement of the phase singularities. Therefore, it cangreatly shorten the imaging time, while calculating the decorrelation ofthe speckle frames can require long imaging time that has to be fewtimes longer than the decorrelation time of the speckles.

Exemplary Results and Discussion of Fiber Bundle Selection

The coupling can be integrated between all guided modes in differentindividual cores of a 7-core structure with specifications of type Ifiber bundle listed in Table 2 above. Since each core in this structurecan support 19 guided modes at a wavelength of about 690 nm, the totalnumber of guided fiber modes can be 7×19=133, and therefore, thedimensions of the matrices of coupling coefficient κ between all modescan be 133 by 133. The amplitudes of the mode coupling coefficients|K_(vμ)| are shown in FIG. 21A. Here the mode index v can run throughall 133 guided modes. It is noted that the first 19 modes, which canpropagate in the central fiber, can have large coupling coefficientswith the higher order modes of all surrounding fibers while the couplingcoefficients between the modes of each of the 6 surrounding fiber andthe modes of its 3 nearest neighbors can be much larger than thecoupling coefficients to the modes of further cores. Thus, the couplingcoefficient of modes of each core can be dominant by the coupling to themodes of its nearest neighbors. FIGS. 21B-21F show the intensity in eachcore, which can be the summation of squared mode amplitudes over allguided modes in the core, which can oscillate between the central fiberand surrounding fiber with propagation distance z. As shown in FIGS.21B-21F, the mode 1, 2, 6, 9, 10 of central fiber can initially beexcited at z=0. The mode amplitudes changing with z up to 1 m which canroughly be a typical length of fiber bundles used in medical endoscopycan then be calculated.

As the order of excited mode of central fiber can increase from 1 to 10as shown in FIGS. 21B-21F, the coupling distance defined as theoscillation period of intensity along with propagation distance zbecomes shorter. The intensity in central core represented by line 2105can't couple to the surrounding cores whose intensity represented bylines 2110 when only the fundamental mode of central core can be excitedas shown in FIG. 21B. While FIG. 21F shows that there can be multiplecoupling distances within 1 m which can indicate strong core-to-corecoupling when only mode 10 of central fiber can be initially excited.For the modes with same order of different identical cores, thedifference between the propagation constant Δβ of these modes can be 0,and the coupling strength may only depend on the mode couplingcoefficient between these modes with same order in each fiber. Since thefields of a higher order modes can extend more into the cladding, theoverlapping of higher order mode field can be stronger, and couplingbetween higher order modes of identical cores can be stronger. For themodes with different order of adjacent cores, due to the difference inpropagation constant, the cross order mode coupling can be neglectedwhich can be observed in FIG. 21F. If there can be cross order modecoupling, the intensity oscillation between central and surround corescan be more complex than the simple one period oscillation shown in FIG.21F. Thus, if the number of guided modes in each fiber can be reduced toless than 10, the coupling between cores can be suppressed.

In order to better understand the effect of different fiber bundlesspecifications on the coupling efficiency of all modes, the totalintensity coupled from central core to surrounding cores along withpropagation distance for the fiber bundles with differentspecifications, including core sizes, core spacings and NA, as shown inFIG. 22, can be investigated. In the exemplary calculation, the initialvalue of amplitudes of all guided N modes of central fiber can be set tobe equal, al(0)=a2(0)= . . . =aN(0)=(1/N)½, and the initial value of themode amplitudes of surrounding fibers can be all set to zeros. Thecoupling between fibers for fiber bundles with 3 different core sizes(e.g., 2 μm, 3 μm and 4 μm), 3 different core spacings (e.g., 6 μm, 7 μmand 8 μm), and 3 different NA, (e.g., 0.22, 0.32 and 0.40) can becalculated. As shown in In FIGS. 22A-22C, coupling strength can bestronger as core sizes increase from 2 μm, 3 μm to 4 μm because thefibers can support more higher order modes whose coupling can be strongand the overlap of lower order mode can also be stronger since they canbe closer when core size increases. FIGS. 22D-22F show that the largecore-to-core spacing can lead to reduced coupling due to the largeseparation between mode fields because of the less mode field overlapswhen the cores can be closer. FIGS. 22G-22I show that the larger NAindicating larger refractive index contrast between core and claddingmaterial can lead to stronger confinement of mode fields and can reduceoverlapping of modal fields of neighboring fibers.

The modulation to the transmitted speckle patterns due to the corecoupling is shown in FIG. 23A-23C. FIGS. 23A-23C show the numericallygenerated speckle patterns, the speckle patterns coupled in the fiberbundle at z=0, and speckle pattern at z=1 m for fiber bundle with 3 μmcore size, 6 μm core spacing and 0.40 NA. Strong modulation of thespeckle patterns can be observed from the difference of speckle patternsin FIGS. 23B and 23C. The ensemble average over 20 speckle realizationof correlation function for fiber bundles with different core sizes,core spacings and NAs are shown in FIGS. 23D-23F, respectively. Thelarge core-to-core separation, small core size and large refractiveindex contrast between core and cladding material can be essential toreliably transmitted speckle patterns. Based on the results shown inFIGS. 22A-22F, and 23A-23I, fiber bundles with 3 μm core size, 8 tm corespacing and 0.40 NA can have moderate crosstalk between fibers, and itsspecifications can be close to those commercially available, such thatit can be relatively easy to manufacture. The fiber with 3 tm core sizecan support 9 modes to avoid strong coupling of higher order diodes. Thetransmitted speckle patterns at z-O, 1 and 100 cm are shown in FIGS.23G-23I, respectively. The modulation of speckle patterns along with zcan be less than the modulation of the speckle patterns shown in FIGS.23B and 23C. It shows again that the relative large separation can helpto suppress core coupling and modulation to speckle patterns. The higherNA can confine mode field in the core better, but higher NA can alsoincrease the number of guided modes and 0.40 NA can be the highestcurrently available contrast of refractive index between core andcladding material of fiber bundles.

An additional parameter that can influence mode coupling can be thenon-uniformity of fibers such as fluctuations of core size and irregularcore shape. This non-uniformity can introduce the mismatch inpropagation constant R between cores and a small amount of mismatch canextensively reduce mode coupling between fibers. (See e.g., References115 and 117). This great reduction can be observed in FIGS. 24B and 24C,in which the total intensity transferred from central fiber tosurrounding fibers for fiber bundles with same core size and 1% and 2%randomness in core size are shown. However even though the fluctuationof core size can introduce mismatch of propagation constants of sameorder modes, it can introduce the possibility that different order modesin adjacent fibers have nearly equal and can cause strong couplingbetween cross order modes of neighboring cores. FIG. 24B shows oneexample that 5th mode of central fiber and 6th mode of one neighboringfiber is almost the same, such that there can be strong coupling betweenthese two modes. Thus it can be important to utilize the non-uniformityto reduce the cross talk between fibers since it can introduce thepossibility of cross order mode coupling. To reduce this possibility,reducing the guided modes of each fiber supported can be performed.

By combining all above exemplary results, the parameters of fiberbundles can include a core diameter of 3.0 μm±0.3 μm, or 3.0 μm±0.2 μm,or 3.0 μm±0.1 μm, or a core diameter of 3.0 μm within measurable error.

The exemplary diameter of the core can have a fluctuation of ±0.02 μm to±0.4 μm; ±0.02 μm to ±0.3 μm, ±0.03 μm to ±0.3 μm; 0.05 μm to ±0.2 μm,or approximately ±0.1 μm. In some embodiments, the core fluctuation canbe approximately 0.06 tm (e.g., 2.0%). An even larger mismatch (e.g.,larger than ±0.4 μm) could also be used to introduce an even largermismatch between modes of the cores. However, such a large mismatch incore fluctuation can preferably be used with smaller core diameters(e.g., a core diameter of 2.7 μm, 2.8 μm, 2.9 μm or 3.0 μm) instead oflarger core diameters. The exemplary bundle specifications can be usedat, and can be based on, a wavelength of between about 630-720 nm. Thebundle specifications can also be dependent on the illuminationwavelength, and can be selected to reduce crosstalk between opticalfibers in the exemplary fiber bundle. In some embodiments, themanufacture of the core can provide for such a fluctuation in the corediameter as inherent in the formation process. Thus, it can be an aspectof the present disclosure that the fluctuation in the core diameter canbe defined by the formation of the fiber bundle. In other embodiments,an increased fluctuation as compared to the minimal fluctuation that canbe formed can be preferred.

The fiber bundle can also include a core spacing of 8.0 μm±0.7 μm, 8.0μm±0.5 μm, 8.0 μm±0.4 μm, 8.0 μm±0.3 μm, 8.0 μm±0.2 μm, or 8.0 μm±0.1μm, or 8.0 μm within measurable error. The fiber bundle can also includea numerical aperture of at least 0.35, at least 0.36, at least 0.37, atleast 0.38, at least 0.39, or at least 0.40. In one embodiment, thenumerical aperture can be between 0.37 and 0.41 or between 0.38 and0.41. While the highest NA for current commercially available fiberoptic bundles can be approximately 0.40, higher NA can be preferred forreducing crosstalk, and the higher NA can be used should they becomeavailable, such as a NA of about 0.42, 0.43, 0.44, or 0.45. In oneembodiment, the fiber bundle has a core diameter of 3.0 μm±0.1 μm withfluctuations in the core size of ±0.1 μm to ±0.2 μm, a core spacing of8.0 μm±0.5 μm, and a numerical aperture of between 0.38 and 0.41.

While there can be variability in each of the parameters as describedherein, it can be understood that each of the parameters can beinterrelated, and if it is desirable to change one parameter in theformation of the optical fiber, it can also be advisable to change oneor more other parameter to compensate for the initial change.

The fiber bundle as described herein can reliably transmit specklepatterns at wavelength 690 nm.

The fiber optic bundles of the present disclosure can have reducedinter-fiber crosstalk. In some embodiments, the reduction in inter-fibercrosstalk at a propagation distance of 0.5 m using 690 nm radiation canbe at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or morecompared to an available fiber optic bundle, such either of the SCHOTTType 1 or SCHOTT Type 2 leached image bundles described in Table 2above. In some embodiments, the inter-fiber crosstalk of the fiber opticbundle can be at a negligible level. While the variance in the fibersize can facilitate that, two adjacent fibers have identical corediameters and thus a relative increase in inter-fiber crosstalk, in someembodiments, the average inter-fiber crosstalk for the fiber opticbundle can be insignificant and provides a near-zero negativecontribution to the image quality.

The exemplary coupled intensity in cores of one configuration of type Iand type II fiber bundles with ±0.1 μm randomness in core size andexemplary fiber bundles according to the present disclosure are shown inFIGS. 25A-25C, respectively. The strong coupling can be seen in bothtype I and type II fiber bundles while the coupling in fiber bundles ofthe present disclosure may not be obvious. When fiber bundles aremoving, the coupling between cores could change with time because themotion can change the mode overlapping and introduce modulation to theextra phase difference between cores due to bending and twisting offiber bundles. (See, e.g., References 124 and 125). However for totallydecoupled cores, the effect of fiber bundles motion can be weak, and canbe neglected. So, to conduct in vivo LSI, a fiber bundle with fullydecoupled cores can be preferred to eliminate the influence of bundlemotion. The fiber bundle, as described herein, has shown the smallcoupling between cores so that it should not be sensitive to the bundlemotion.

Optical fiber bundles have been demonstrated to be a key component toconduct endoscopic LSI. The transmitted laser speckles can be modulatedby inter-fiber coupling reducing the accuracy of speckle temporalstatistics. As described herein, coupled mode theory can be applied, andthe influence of fiber core size, core spacing, numerical aperture andvariations in core size on mode coupling and speckle modulation has beenanalyzed. The analysis of the speckle intensity autocorrelation oftime-resolved speckle frames illustrated that a fiber bundle with about3±0.1 μm core size, about 81 im core spacing and about 0.40 NA, canfacilitate reliable speckle transmission to conduct endoscopic LSI atabout 690 nm. The exemplary results can provide solutions andrecommendations for the design, selection and optimization of fiberbundles to conduct endoscopic LSI.

FIG. 40 shows a block diagram of an exemplary embodiment of a systemaccording to the present disclosure. For example, exemplary proceduresin accordance with the present disclosure described herein can beperformed by a processing arrangement and/or a computing arrangement4002. Such processing/computing arrangement 4002 can be, for exampleentirely or a part of, or include, but not limited to, acomputer/processor 4004 that can include, for example one or moremicroprocessors, and use instructions stored on a computer-accessiblemedium (e.g., RAM, ROM, hard drive, or other storage device).

As shown in FIG. 40, for example a computer-accessible medium 4006(e.g., as described herein above, a storage device such as a hard disk,floppy disk, memory stick, CD-ROM, RAM, ROM, etc., or a collectionthereof) can be provided (e.g., in communication with the processingarrangement 4002). The computer-accessible medium 4006 can containexecutable instructions 4008 thereon. In addition or alternatively, astorage arrangement 4010 can be provided separately from thecomputer-accessible medium 4006, which can provide the instructions tothe processing arrangement 4002 so as to configure the processingarrangement to execute certain exemplary procedures, processes andmethods, as described herein above, for example.

Further, the exemplary processing arrangement 4002 can be provided withor include an input/output arrangement 4014, which can include, forexample a wired network, a wireless network, the internet, an intranet,a data collection probe, a sensor, etc. As shown in FIG. 40, theexemplary processing arrangement 4002 can be in communication with anexemplary display arrangement 4012, which, according to certainexemplary embodiments of the present disclosure, can be a touch-screenconfigured for inputting information to the processing arrangement inaddition to outputting information from the processing arrangement, forexample. Further, the exemplary display 4012 and/or a storagearrangement 4010 can be used to display and/or store data in auser-accessible format and/or user-readable format.

The foregoing merely illustrates the principles of the disclosure.Various modifications and alterations to the described embodiments willbe apparent to those skilled in the art in view of the teachings herein.It will thus be appreciated that those skilled in the art will be ableto devise numerous systems, arrangements, and procedures which, althoughnot explicitly shown or described herein, embody the principles of thedisclosure and can be thus within the spirit and scope of thedisclosure. Various different exemplary embodiments can be used togetherwith one another, as well as interchangeably therewith, as should beunderstood by those having ordinary skill in the art. In addition,certain terms used in the present disclosure, including thespecification, drawings and claims thereof, can be used synonymously incertain instances, including, but not limited to, for example, data andinformation. It should be understood that, while these words, and/orother words that can be synonymous to one another, can be usedsynonymously herein, that there can be instances when such words can beintended to not be used synonymously. Further, to the extent that theprior art knowledge has not been explicitly incorporated by referenceherein above, it is explicitly incorporated herein in its entirety. Allpublications referenced are incorporated herein by reference in theirentireties.

EXEMPLARY REFERENCES

The following references are hereby incorporated by reference in theirentirety.

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1.-20. (canceled)
 21. A catheter system for obtaining informationregarding at least one biological sample, comprising: at least one fiberthrough which at least one electromagnetic radiation is propagated tothe at least one biological sample; a multi-faceted mirror havingmultiple surfaces arranged with respect to the at least one fiber tosimultaneously receive the at least one electromagnetic radiation ateach of the multiple surfaces and deliver reflected radiation thatincludes speckle patterns; and a fiber bundle configured to receive,from the multi-faceted mirror, a reflected radiation that includes thespeckle patterns from the multiple surfaces of the multi-faceted mirror,wherein the fiber bundle is further configured to deliver the reflectedradiation obtained, via the multiple surfaces of the multi-facetedmirror, from the at least one biological sample at multiple illuminationlocations to a detector to image the speckle patterns from the at leastone biological sample at the multiple illumination locations based onthe reflected radiation.
 22. The system of claim 21, wherein the fiberbundle is further configured to deliver the reflected radiationobtained, via the multiple surfaces of the multi-faceted mirror, withouta rotation of the at least one fiber, the multi-faceted mirror, or thefiber bundle.
 23. The system of claim 21, wherein the multiple surfacesof the multi-faceted mirror include more than two surfaces.
 24. Thesystem of claim 21, wherein the multi-faceted mirror forms a shape of atleast one of a cone, a polygon, or a pyramid.
 25. The system of claim21, wherein the at least one biological sample comprises at least one ofblood or blood cells.
 26. The system of claim 21, wherein the at leastone biological sample comprises an in-vivo vessel and the fiber bundleis configured to receive the reflected radiation from over acircumference of the in-vivo vessel.
 27. The system of claim 26, furthercomprising a pullback arrangement which, during delivery of thereflected radiation to the multiple illumination locations, isconfigured to pull back the at least one of the at least one fiber andthe fiber bundle to adjust a position of the multiple illuminationlocations across the at least one biological sample to obtaininformation about the circumference and along a length of the in-vivovessel.
 28. The system of claim 21, further comprising at least onesplitter coupled to the at least one fiber to split the light atdifferent wavelengths before arriving at the multi-faceted mirror, andwherein the fiber bundle is further configured to receive the reflectedradiation at the different wavelengths.
 29. The system of claim 21,further comprising at least one of a lens, a GRIN lens, a ball lens, oran imaging lens coupled to the at least one fiber to receive the lightbefore being propagated to the at least one biological sample.
 30. Thesystem of claim 21, wherein the multi-faceted mirror having multiplesurfaces is further configured to deliver reflected radiation thatincludes speckle patterns having an intensity that varies in time. 31.The system of claim 30, wherein the multi-faceted mirror having multiplesurfaces is further configured to deliver reflected radiation whilemaintaining variations of the intensity of the speckle patterns toprovide information regarding mechanical properties of the at least onebiological sample.
 32. The system of claim 21, further comprising aprocessor configured to determine viscoelastic properties of the atleast one biological sample based on the speckle patterns from the atleast one biological sample.
 33. A catheter system for obtaininginformation regarding an in-vivo vessel, comprising: at least one fiberthrough which light is propagated to the in-vivo vessel; a reflectorhaving multiple surfaces and arranged with respect to the at least onefiber to simultaneously receive the light at each of the multiplesurfaces and simultaneously deliver reflected light that induces specklepatterns in the in-vivo vessel that are directed back to the reflector;and a fiber bundle configured to receive, from the reflector, thespeckle patterns induced by the reflected light that includes thespeckle patterns induced by the reflected light from the multiplesurfaces of the reflector, wherein the fiber bundle is furtherconfigured to deliver the reflected light obtained, via the multiplesurfaces of the reflector, from over a circumference of the in-vivovessel to a detector to image the speckle patterns from thecircumference of the in-vivo vessel based on the reflected light. 34.The system of claim 33, wherein the fiber bundle is further configuredto deliver the reflected light obtained, via the multiple surfaces ofthe reflector, without a rotation of the at least one fiber, thereflector, or the fiber bundle.
 35. The system of claim 33, wherein themultiple surfaces of the reflector include more than two surfaces. 36.The system of claim 33, wherein the reflector forms a shape of at leastone of a cone, a polygon, or a pyramid.
 37. The system of claim 33,wherein the in-vivo vessel comprises at least one of blood or bloodcells.
 38. The system of claim 33, further comprising a pullbackarrangement which, during delivery of the reflected light to themultiple illumination locations, is configured to pull back the at leastone of the at least one fiber and the fiber bundle to adjust a positionof the multiple illumination locations across the in-vivo vessel toobtain information about the circumference and along a length of thein-vivo vessel.
 39. The system of claim 33, further comprising at leastone splitter coupled to the at least one fiber to split the light atdifferent wavelengths before arriving at the reflector, and wherein thefiber bundle is further configured to receive the reflected light at thedifferent wavelengths.
 40. The system of claim 33, further comprising atleast one of a lens, a GRIN lens, a ball lens, or an imaging lenscoupled to the at least one fiber to receive the light before beingpropagated to the in-vivo vessel.
 41. The system of claim 33, whereinthe reflector having multiple surfaces is further configured to deliverreflected light that includes speckle patterns having an intensity thatvaries in time.
 42. The system of claim 41, wherein the reflector havingmultiple surfaces is further configured to deliver reflected light whilemaintaining variations of the intensity of the speckle patterns toprovide information regarding mechanical properties of the in-vivovessel.